Table Info

Table 1.

A list of 20 subfamilies of human RTKs along with their family members and respective extracellular and intracellular domains

Family name	Members	Ligands	Extracellular domain	Intracellular domain	γ-secretase cleavage	Nuclear localization status	Mechanism of nuclear localization
EGFR	ErbB1, ErbB2, ErbB3, ErbB4*	EGF, transforming GF A (TGFA), heparin-binding EGF-like GF (HBEGF), betacellulin (BTC), Amphiregulin (AREG), epiregulin (EREG), epigen (EPGN)	2-Cysteine rich domains	JM domain, tyrosine kinase domain, a C-terminal regulatory region	Yes	Yes	Clathrin mediated endocytosis [35], retro-translocation by ER-associated trafficking machinery [36], nuclear localization signals (NLS) sequence [34]
InsR	InsR, IGF1R**, IRR	INS-like GF-1 (IGF-1), IGF-2, INS	2-Chains α and β, 2-leucine rich domain separated by a cysteine rich domain, 3-fibronectin type III (FNIII) domains	Tyrosine kinase domain	Yes	Yes	The possible mechanism includes SUMOylation/via microtubules with the help of some proteins [p150Glued, AREG, importin-β, ran-binding protein 2 (RanBP2)] or clathrin mediated endocytosis [37], NLS
PDGFR	PDGFRα, PDGFRβ, Kit, fibromyalgia syndrome-like tyrosine kinase 3 ligand (FLT3L), colony stimulating factor 1 (CSF1)*	Platelet-derived GF (PDGF), PDGF-A, PDGF-AA, PDGF-AB, PDGF-AB/BB, PDGF-B, PDGF-BB, PDGF-C, PDGF-CC, PDGF-D, PDGF-DD	5-Ig-like domains	JM domain, tyrosine kinase containing a long kinase insert domain region, a C-terminal extension	Yes	Yes	Mediated by clathrin coated pits, β-importin, via TATA element modulatory factor 1 (TMF1) positive Golgi vesicles [38]
VEGFR	VEGFR1, VEGFR2, VEGFR3***	Vascular endothelial GF (VEGF)-A, VEGF-B, neuropilin-1, placental GF (PlGF), VEGF-C, VEGF-D	7-Ig-like domains	JM domain, tyrosine kinase domain	Yes	Yes	Mediated by VEGF stimulation and complex formation with tissue transglutaminase II for endothelial cells [39], endocytosis [40]
FGFR	FGFR1, FGFR2, FGFR3, FGFR4**	Fibroblast GF (FGF) 1–22	3-Ig-like domains	JM region, tyrosine kinase domain	Yes	Yes	Importin-β-mediated interferons (INFS) mechanism [34] clathrin mediated endocytosis [41]
CCK	CCK4/PTK7*	Coreceptor for Wnt signaling	7-Ig domains	Catalytic domain lacking tyrosine kinase activity	Yes	Yes	-
NGFR	TRKA, TRKB, TRKC**	NGF, BDNF, Neurotrophin 3 (NT3), NT4	3-Leucine repeats flanked by cysteine clusters and 2-Ig-like domains	Tyrosine kinase domain	Yes	Yes	Mediated by Carrier vesicles [42], NLS, and phosphorylation dependent process [43], mediated by importins [44]
Hepatocyte GF receptor (HGFR)	MET, Recepteur d’ origine nantais (RON)*	Hepatocyte GF (HGF)	Sema domain, a PSI domain, and 4-Ig-like plexins transcription factors (IPT) domains	JM domain, tyrosine kinase domain, carboxy-terminal tail region	Yes	Yes	Mediated by Gab1 and importin-β, NLS [43], integral trafficking from ER to the nuclear envelop transport (INTERNET) [34]
Erythropoietin-producing human hepatocellular receptor (EPHR)	EPHA1, EPHA2, EPHA3, EPHA4, EPHA5*, EPHA6, EPHA7*, EPHA8, EPHA10, EPHB1, EPHB2**, EPHB3, EPHB4, EPHB6	Ephrin A (1–5), ephrin B (1–3)	Cysteine-rich domain and 2 FNIII repeats	Tyrosine kinase domain	Yes	Yes	pH-Dependent nuclear localization signal [34]
Axl	Axl, Mer, TYRO3***	Growth arrest specific gene 6 (Gas 6)	2-Ig-like domains and 2-FNIII domains	Tyrosine kinase domain	Yes	Yes	NLS [45]
Tie	Tie, TEK*	Angiopoietin (ANG) GFs (ANG1, ANG2, ANG4)	2-Ig-like, 1-EGF, 3-FNIII domains	Tyrosine kinase domain	Yes	Yes	Caveolin mediated nuclear translocation [46]
RYK	RYK*	Wnt1, Wnt3a	Leucine-rich domain with a WIF-type Wnt binding region	Tyrosine kinase domain lacking kinase activity	Yes	Yes	Chaperone mediated, suppressor of Mek null 1/2 (smek1/2) functions as a chaperone and regulates nuclear translocation [47]
DDR	DDR1, DDR2	Collagen (I, IV, V, VI, VIII), collagen (I, III, X)	Discoidin domain, discoidin-like domain, extracellular juxtamembrane region	JM domain, tyrosine kinase domain	-	Yes	Stimulation with collagen leads to interaction with Sec61 translocon subunit beta (SEC61B) and results in nuclear translocation [48]
ROS	ROS	-	6-FNIII like domains	Tyrosine kinase domain	-	-	-
Leukocyte tyrosine kinase (LTK)	LTK, ALK	ALK and LTK ligand 1 (ALKAL1), ALKAL2	2-Meprin A-5 protein and receptor protein phosphatase mu (2-MAM) domains 1-Ldla motif, cysteine rich and glycine rich domains	JM domain, tyrosine kinase domain	-	-	-
ROR	ROR1, ROR2	Wnt5a	Ig-domain, cysteine-rich domains, and kringle-like domains	Tyrosine kinase domain, proline-rich, serine-threonine rich domains	-	Yes	Cleavage releasing mechanism in addition to Ran-GTPase pathway [45]
MUSK	MUSK*	Agrin	3-Ig-like and 1-cysteine rich frizzled-like domain	A JM domain, a kinase domain, and a short cytoplasmic tail	Yes	-	-
LMR	Apoptosis associated tyrosine kinase (AATYK), AATYK, AATYK3		A short extracellular domain containing leucine residues	Tyrosine kinase domain	-	-	-
Ret	Ret	Glial cell line-derived neurotrophic factor (GDNF), neuturin, artemin, persephin, growth differentiation factor-15 (GDF-15)	4-Cadherin like domain, a cysteine rich domain	JM domain, kinase domain, a C-terminal tail	-	Yes	-
STYK1	STYK1	-	It has a truncated extracellular domain, a single transmembrane domain	A relatively short intracellular domain possessing tyrosine kinase activity	-	-	-

The RTKs marked in asterisks (*) are reported to be cleaved by the γ-secretase enzyme [49, 50], and those in bold text are known to have nuclear localization. Noticeably, some of the RTKs undergo both γ-secretase cleavage and nuclear localization. -: no information is available as of now

Declarations

Author contributions

PS: Conceptualization, Writing—original draft, Writing—review & editing. RD: Conceptualization, Writing—original draft, Writing—review & editing. PM: Conceptualization, Writing—original draft. DM: Conceptualization.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

The research is funded by the Department of Atomic Energy, Government of India [RSI4002]. The funders did not have any role in study design, collection of data and analysis, preparation of the manuscript or the decision to publish.

Copyright

References

Chung I. Optical measurement of receptor tyrosine kinase oligomerization on live cells. Biochim Biophys Acta Biomembr. 2017;1859:1436–44. [DOI] [PubMed]

Du Z, Lovly CM. Mechanisms of receptor tyrosine kinase activation in cancer. Mol Cancer. 2018;17:58. [DOI] [PubMed] [PMC]

Hausott B, Kurnaz I, Gajovic S, Klimaschewski L. Signaling by neuronal tyrosine kinase receptors: relevance for development and regeneration. Anat Rec. 2009;292:1976–85. [DOI] [PubMed]

Huang EJ, Reichardt LF. Neurotrophins: roles in neuronal development and function¹. Annu Rev Neurosci. 2001;24:677–736. [DOI] [PubMed] [PMC]

Kornblum HI, Hussain R, Wiesen J, Miettinen P, Zurcher SD, Chow K, et al. Abnormal astrocyte development and neuronal death in mice lacking the epidermal growth factor receptor. J Neurosci Res. 1998;53:697–717. [DOI] [PubMed]

Gupta R, Sahu M, Srivastava D, Tiwari S, Ambasta RK, Kumar P. Post-translational modifications: regulators of neurodegenerative proteinopathies. Ageing Res Rev. 2021;68:101336. [DOI] [PubMed]

Smith BJ, Carregari VC. Post-translational modifications during brain development. Adv Exp Med Biol. 2022;1382:29–38. [DOI] [PubMed]

Qu W, Yuan B, Liu J, Liu Q, Zhang X, Cui R, et al. Emerging role of AMPA receptor subunit GluA1 in synaptic plasticity: implications for Alzheimer’s disease. Cell Prolif. 2021;54:e12959. [DOI] [PubMed] [PMC]

Taoro-González L, Cabrera-Pastor A, Sancho-Alonso M, Felipo V. Intracellular and extracelluar cyclic GMP in the brain and the hippocampus. Vitam Horm. 2022;118:247–88. [DOI] [PubMed]

10.

Wang G, Li S, Gilbert J, Gritton HJ, Wang Z, Li Z, et al. Crucial roles for SIRT2 and AMPA receptor acetylation in synaptic plasticity and memory. Cell Rep. 2017;20:1335–47. [DOI] [PubMed] [PMC]

11.

Moutin MJ, Bosc C, Peris L, Andrieux A. Tubulin post-translational modifications control neuronal development and functions. Dev Neurobiol. 2021;81:253–72. [DOI] [PubMed] [PMC]

12.

Moujaber O, Stochaj U. The cytoskeleton as regulator of cell signaling pathways. Trends Biochem Sci. 2020;45:96–107. [DOI] [PubMed]

13.

Hall A. Rho GTPases and the actin cytoskeleton. Science. 1998;279:509–14. [DOI] [PubMed]

14.

Majumder P, Chanda K, Das D, Singh BK, Chakrabarti P, Jana NR, et al. A nexus of miR-1271, PAX4 and ALK/RYK influences the cytoskeletal architectures in Alzheimer’s disease and type 2 diabetes. Biochem J. 2021;478:3297–317. [DOI] [PubMed] [PMC]

15.

Kong P, Lei P, Zhang S, Li D, Zhao J, Zhang B. Integrated microarray analysis provided a new insight of the pathogenesis of Parkinson’s disease. Neurosci Lett. 2018;662:51–8. [DOI] [PubMed]

16.

Kang SS, Zhang Z, Liu X, Manfredsson FP, Benskey MJ, Cao X, et al. TrkB neurotrophic activities are blocked by α-synuclein, triggering dopaminergic cell death in Parkinson’s disease. Proc Natl Acad Sci U S A. 2017;114:10773–8. [DOI] [PubMed] [PMC]

17.

Sastre AA, Montoro ML, Gálvez-Martín P, Lacerda HM, Lucia AM, Llavero F, et al. Small GTPases of the Ras and Rho families switch on/off signaling pathways in neurodegenerative diseases. Int J Mol Sci. 2020;21:6312. [DOI] [PubMed] [PMC]

18.

García-García R, Martín-Herrero L, Blanca-Pariente L, Pérez-Cabello J, Roodveldt C. Immune signaling kinases in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Int J Mol Sci. 2021;22:13280. [DOI] [PubMed] [PMC]

19.

Pasquale EB. Eph-ephrin bidirectional signaling in physiology and disease. Cell. 2008;133:38–52. [DOI] [PubMed]

20.

Van Hoecke A, Schoonaert L, Lemmens R, Timmers M, Staats KA, Laird AS, et al. EPHA4 is a disease modifier of amyotrophic lateral sclerosis in animal models and in humans. Nat Med. 2012;18:1418–22. [DOI] [PubMed]

21.

Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2000;103:211–25. [DOI] [PubMed]

22.

Lemmon MA, Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2010;141:1117–34. [DOI] [PubMed] [PMC]

23.

Robinson DR, Wu YM, Lin SF. The protein tyrosine kinase family of the human genome. Oncogene. 2000;19:5548–57. [DOI] [PubMed]

24.

Siveen KS, Prabhu KS, Achkar IW, Kuttikrishnan S, Shyam S, Khan AQ, et al. Role of non receptor tyrosine kinases in hematological malignances and its targeting by natural products. Mol Cancer. 2018;17:31. [DOI] [PubMed] [PMC]

25.

Maruyama IN. Mechanisms of activation of receptor tyrosine kinases: monomers or dimers. Cells. 2014;3:304–30. [DOI] [PubMed] [PMC]

26.

van Obberghen E. Signalling through the insulin receptor and the insulin-like growth factor-I receptor. Diabetologia. 1994;37:S125–34. [DOI] [PubMed]

27.

Butti R, Das S, Gunasekaran VP, Yadav AS, Kumar D, Kundu GC. Receptor tyrosine kinases (RTKs) in breast cancer: signaling, therapeutic implications and challenges. Mol Cancer. 2018;17:34. [DOI] [PubMed] [PMC]

28.

Wagner MJ, Stacey MM, Liu BA, Pawson T. Molecular mechanisms of SH2- and PTB-domain-containing proteins in receptor tyrosine kinase signaling. Cold Spring Harb Perspect Biol. 2013;5:a008987. [DOI] [PubMed] [PMC]

29.

Pawson T, Scott JD. Signaling through scaffold, anchoring, and adaptor proteins. Science. 1997;278:2075–80. [DOI] [PubMed]

30.

Luo LY, Hahn WC. Oncogenic signaling adaptor proteins. J Genet Genomics. 2015;42:521–9. [DOI] [PubMed] [PMC]

31.

Rivero-Lezcano OM, Marcilla A, Sameshima JH, Robbins KC. Wiskott-Aldrich syndrome protein physically associates with Nck through Src homology 3 domains. Mol Cell Biol. 1995;15:5725–31. [DOI] [PubMed] [PMC]

32.

Schiller MR. Coupling receptor tyrosine kinases to Rho GTPases–GEFs what’s the link. Cell Signal. 2006;18:1834–43. [DOI] [PubMed]

33.

Islam MI, Nagakannan P, Shcholok T, Contu F, Mai S, Albensi BC, et al. Regulatory role of cathepsin L in induction of nuclear laminopathy in Alzheimer’s disease. Aging Cell. 2022;21:e13531. [DOI] [PubMed] [PMC]

34.

Chen MK, Hung MC. Proteolytic cleavage, trafficking, and functions of nuclear receptor tyrosine kinases. FEBS J. 2015;282:3693–721. [DOI] [PubMed] [PMC]

35.

Wang YN, Yamaguchi H, Hsu JM, Hung MC. Nuclear trafficking of the epidermal growth factor receptor family membrane proteins. Oncogene. 2010;29:3997–4006. [DOI] [PubMed] [PMC]

36.

Wang SC, Hung MC. Nuclear translocation of the EGFR family membrane tyrosine kinase receptors. Clin Cancer Res. 2009;15:6484–9. [DOI] [PubMed] [PMC]

37.

Poreba E, Durzynska J. Nuclear localization and actions of the insulin-like growth factor 1 (IGF-1) system components: transcriptional regulation and DNA damage response. Mutat Res Rev Mutat Res. 2020;784:108307. [DOI] [PubMed]

38.

Papadopoulos N, Lennartsson J, Heldin CH. PDGFRβ translocates to the nucleus and regulates chromatin remodeling via TATA element–modifying factor 1. J Cell Biol. 2018;217:1701–17. [DOI] [PubMed] [PMC]

39.

Dardik R, Inbal A. Complex formation between tissue transglutaminase II (tTG) and vascular endothelial growth factor receptor 2 (VEGFR-2): proposed mechanism for modulation of endothelial cell response to VEGF. Exp Cell Res. 2006;312:2973–82. [DOI] [PubMed]

40.

Zhang Z, Neiva KG, Lingen MW, Ellis LM, Nör JE. VEGF-dependent tumor angiogenesis requires inverse and reciprocal regulation of VEGFR1 and VEGFR2. Cell Death Differ. 2010;17:499–512. [DOI] [PubMed] [PMC]

41.

Chen MK, Hsu JL, Hung MC. Nuclear receptor tyrosine kinase transport and functions in cancer. Adv Cancer Res. 2020;147:59–107. [DOI] [PubMed]

42.

Gong A, Zhang Z, Xiao D, Yang Y, Wang Y, Chen Y. Localization of phosphorylated TrkA in carrier vesicles involved in its nuclear translocation in U251 cell line. Sci China C Life Sci. 2007;50:141–6. [DOI] [PubMed]

43.

Fonseca-Gomes J, Jerónimo-Santos A, Lesnikova A, Casarotto P, Castrén E, Sebastião AM, et al. TrkB-ICD fragment, originating from BDNF receptor cleavage, is translocated to cell nucleus and phosphorylates nuclear and axonal proteins. Front Mol Neurosci. 2019;12:4. [DOI] [PubMed] [PMC]

44.

Ménard M, Costechareyre C, Ichim G, Blachier J, Neves D, Jarrosson-Wuilleme L, et al. Hey1- and p53-dependent TrkC proapoptotic activity controls neuroblastoma growth. PLoS Biol. 2018;16:e2002912. [DOI] [PubMed] [PMC]

45.

Tseng HC, Lyu PC, Lin WC. Nuclear localization of orphan receptor protein kinase (Ror1) is mediated through the juxtamembrane domain. BMC Cell Biol. 2010;11:48. [DOI] [PubMed] [PMC]

46.

Hossain MB, Shifat R, Li J, Luo X, Hess KR, Rivera-Molina Y, et al. TIE2 associates with caveolae and regulates caveolin-1 to promote their nuclear translocation. Mol Cell Biol. 2017;37:e00142-17. [DOI] [PubMed] [PMC]

47.

Chang WH, Choi SH, Moon BS, Cai M, Lyu J, Bai J, et al. Smek1/2 is a nuclear chaperone and cofactor for cleaved Wnt receptor Ryk, regulating cortical neurogenesis. Proc Natl Acad Sci U S A. 2017;114:E10717–25. [DOI] [PubMed] [PMC]

48.

Chiusa M, Hu W, Liao HJ, Su Y, Borza CM, de Caestecker MP, et al. The extracellular matrix receptor discoidin domain receptor 1 regulates collagen transcription by translocating to the nucleus. J Am Soc Nephrol. 2019;30:1605–24. [DOI] [PubMed] [PMC]

49.

Merilahti JAM, Ojala VK, Knittle AM, Pulliainen AT, Elenius K. Genome-wide screen of gamma-secretase–mediated intramembrane cleavage of receptor tyrosine kinases. Mol Biol Cell. 2017;28:3123–31. [DOI] [PubMed] [PMC]

50.

Merilahti JAM, Elenius K. Gamma-secretase-dependent signaling of receptor tyrosine kinases. Oncogene. 2019;38:151–63. [DOI] [PubMed] [PMC]

51.

Guo YJ, Pan WW, Liu SB, Shen ZF, Xu Y, Hu LL. ERK/MAPK signalling pathway and tumorigenesis. Exp Ther Med. 2020;19:1997–2007. [DOI] [PubMed] [PMC]

52.

Soares-Silva M, Diniz FF, Gomes GN, Bahia D. The mitogen-activated protein kinase (MAPK) pathway: role in immune evasion by trypanosomatids. Front Microbiol. 2016;7:183. [DOI] [PubMed] [PMC]

53.

LLowenstein EJ, Daly RJ, Batzer AG, Li W, Margolis B, Lammers R, et al. The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling. Cell. 1992;70:431–42. [DOI] [PubMed]

54.

Kim EK, Choi EJ. Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta. 2010;1802:396–405. [DOI] [PubMed]

55.

Hemmings BA, Restuccia DF. PI3K-PKB/Akt Pathway. Cold Spring Harb Perspect Biol. 2012;4:a011189. [DOI] [PubMed] [PMC]

56.

Porta C, Paglino C, Mosca A. Targeting PI3K/Akt/mTOR signaling in cancer. Front Oncol. 2014;4:64. [DOI] [PubMed] [PMC]

57.

Koundouros N, Poulogiannis G. Phosphoinositide 3-kinase/Akt signaling and redox metabolism in cancer. Front Oncol. 2018;8:160. [DOI] [PubMed] [PMC]

58.

Razani E, Pourbagheri-Sigaroodi A, Safaroghli-Azar A, Zoghi A, Shanaki-Bavarsad M, Bashash D. The PI3K/Akt signaling axis in Alzheimer’s disease: a valuable target to stimulate or suppress? Cell Stress Chaperones. 2021;26:871–87. [DOI] [PubMed] [PMC]

59.

Kania E, Roest G, Vervliet T, Parys JB, Bultynck G. IP₃ receptor-mediated calcium signaling and its role in autophagy in cancer. Front Oncol. 2017;7:140. [DOI] [PubMed] [PMC]

60.

Thatcher JD. The inositol trisphosphate (IP₃) signal transduction pathway. Sci Signal. 2010;3:tr3. [DOI] [PubMed]

61.

Haas E, Stanley DW. Phospholipases. In: Enna SJ, Bylund DB, editors. XPharm: The comprehensive pharmacology reference. New York: Elsevier; 2007. pp. 1–3.

62.

Pchitskaya E, Popugaeva E, Bezprozvanny I. Calcium signaling and molecular mechanisms underlying neurodegenerative diseases. Cell Calcium. 2018;70:87–94. [DOI] [PubMed] [PMC]

63.

Stutzmann GE. Calcium dysregulation, IP3 signaling, and Alzheimer’s disease. Neuroscientist. 2005;11:110–5. [DOI] [PubMed]

64.

Seif F, Khoshmirsafa M, Aazami H, Mohsenzadegan M, Sedighi G, Bahar M. The role of JAK-STAT signaling pathway and its regulators in the fate of T helper cells. Cell Commun Signal. 2017;15:23. [DOI] [PubMed] [PMC]

65.

Massagué J. TGFβ signalling in context. Nat Rev Mol Cell Biol. 2012;13:616–30. [DOI] [PubMed] [PMC]

66.

Liu S, Chen S, Zeng J. TGF-β signaling: a complex role in tumorigenesis (Review). Mol Med Rep. 2018;17:699–704. [DOI] [PubMed]

67.

von Bernhardi R, Cornejo F, Parada GE, Eugenín J. Role of TGFβ signaling in the pathogenesis of Alzheimer’s disease. Front Cell Neurosci. 2015;9:426. [DOI] [PubMed] [PMC]

68.

Yuan Y, Li M, To CH, Lam TC, Wang P, Yu Y, et al. The role of the RhoA/ROCK signaling pathway in mechanical strain-induced scleral myofibroblast differentiation. Invest Ophthalmol Vis Sci. 2018;59:3619–29. [DOI] [PubMed]

69.

Hammar E, Tomas A, Bosco D, Halban PA. Role of the Rho-ROCK (Rho-associated kinase) signaling pathway in the regulation of pancreatic β-cell function. Endocrinology. 2009;150:2072–9. [DOI] [PubMed]

70.

Cai R, Wang Y, Huang Z, Zou Q, Pu Y, Yu C, et al. Role of RhoA/ROCK signaling in Alzheimer’s disease. Behav Brain Res. 2021;414:113481. [DOI] [PubMed]

71.

Liou GY, Storz P. Reactive oxygen species in cancer. Free Radic Res. 2010;44:479–96. [DOI] [PubMed] [PMC]

72.

Sylow L, Jensen TE, Kleinert M, Højlund K, Kiens B, Wojtaszewski J, et al. Rac1 signaling is required for insulin-stimulated glucose uptake and is dysregulated in insulin-resistant murine and human skeletal muscle. Diabetes. 2013;62:1865–75. [DOI] [PubMed] [PMC]

73.

Xie L, Helmerhorst E, Taddei K, Plewright B, Van Bronswijk W, Martins R. Alzheimer’s β-amyloid peptides compete for insulin binding to the insulin receptor. J Neurosci. 2002;22:RC221. [DOI] [PubMed] [PMC]

74.

Zinkle A, Mohammadi M. A threshold model for receptor tyrosine kinase signaling specificity and cell fate determination. F1000Res. 2018;7:872. [DOI] [PubMed] [PMC]

75.

Neben CL, Lo M, Jura N, Klein OD. Feedback regulation of RTK signaling in development. Dev Biol. 2019;447:71–89. [DOI] [PubMed] [PMC]

76.

Kiyatkin A, van Alderwerelt van Rosenburgh IK, Klein DE, Lemmon MA. Kinetics of receptor tyrosine kinase activation define ERK signaling dynamics. Sci Signal. 2020;13:eaaz5267. [DOI] [PubMed] [PMC]

77.

Igietseme JU, Partin J, George Z, Omosun Y, Goldstein J, Joseph K, et al. Epidermal growth factor receptor and transforming growth factor β signaling pathways cooperate to mediate Chlamydia pathogenesis. Infect Immun. 2020;88:e00819-19. [DOI] [PubMed] [PMC]

78.

Lee KJ, Kim Y, Kim MS, Ju HM, Choi B, Lee H, et al. CD99–PTPN12 Axis suppresses actin cytoskeleton-mediated dimerization of epidermal growth factor receptor. Cancers (Basel). 2020;12:2895. [DOI] [PubMed] [PMC]

79.

Naegle KM, White FM, Lauffenburger DA, Yaffe MB. Robust co-regulation of tyrosine phosphorylation sites on proteins reveals novel protein interactions. Mol Biosyst. 2012;8:2771–8. [DOI] [PubMed] [PMC]

80.

Digiacomo G, Tusa I, Bacci M, Cipolleschi MG, dello Sbarba P, Rovida E. Fibronectin induces macrophage migration through a SFK-FAK/CSF-1R pathway. Cell Adh Migr. 2017;11:327–37. [DOI] [PubMed] [PMC]

81.

Maldonado H, Calderon C, Burgos-Bravo F, Kobler O, Zuschratter W, Ramirez O, et al. Astrocyte-to-neuron communication through integrin-engaged Thy-1/CBP/Csk/Src complex triggers neurite retraction via the RhoA/ROCK pathway. Biochim Biophys Acta Mol Cell Res. 2017;1864:243–54. [DOI] [PubMed]

82.

Alam N, Goel HL, Zarif MJ, Butterfield JE, Perkins HM, Sansoucy BG, et al. The integrin—growth factor receptor duet. J Cell Physiol. 2007;213:649–53. [DOI] [PubMed]

83.

Cooper J, Giancotti FG. Integrin signaling in cancer: mechanotransduction, stemness, epithelial plasticity, and therapeutic resistance. Cancer Cell. 2019;35:347–67. [DOI] [PubMed] [PMC]

84.

Sarker FA, Prior VG, Bax S, O’Neill GM. Forcing a growth factor response–tissue-stiffness modulation of integrin signaling and crosstalk with growth factor receptors. J Cell Sci. 2020;133:jcs242461. [DOI] [PubMed]

85.

Jones MC, Zha J, Humphries MJ. Connections between the cell cycle, cell adhesion and the cytoskeleton. Philos Trans R Soc Lond B Biol Sci. 2019;374:20180227. [DOI] [PubMed] [PMC]

86.

Ménard L, Parker PJ, Kermorgant S. Receptor tyrosine kinase c-Met controls the cytoskeleton from different endosomes via different pathways. Nat Commun. 2014;5:3907. [DOI] [PubMed]

87.

Hasenauer S, Malinger D, Koschut D, Pace G, Matzke A, von Au A, et al. Internalization of met requires the co-receptor CD44v6 and its link to ERM proteins. PLoS One. 2013;8:e62357. Erratum in: PLoS One. 2013;8. [DOI] [PubMed] [PMC]

88.

Li R, Knight JF, Park M, Pendergast AM. Abl kinases regulate HGF/Met signaling required for epithelial cell scattering, tubulogenesis and motility. PLoS One. 2015;10:e0124960. [DOI] [PubMed] [PMC]

89.

Banon-Rodriguez I, Saez de Guinoa J, Bernardini A, Ragazzini C, Fernandez E, Carrasco YR, et al. WIP regulates persistence of cell migration and ruffle formation in both mesenchymal and amoeboid modes of motility. PLoS One. 2013;8:e70364. [DOI] [PubMed] [PMC]

90.

Park I, Lee HS. EphB/ephrinB signaling in cell adhesion and migration. Mol Cells. 2015;38:14–9. [DOI] [PubMed] [PMC]

91.

Bernitt E, Döbereiner HG, Gov NS, Yochelis A. Fronts and waves of actin polymerization in a bistability-based mechanism of circular dorsal ruffles. Nat Commun. 2017;8:15863. [DOI] [PubMed] [PMC]

92.

Sentürk A, Pfennig S, Weiss A, Burk K, Acker-Palmer A. Ephrin Bs are essential components of the Reelin pathway to regulate neuronal migration. Nature. 2011;472:356–60. [DOI] [PubMed]

93.

Mulder C, Prust N, van Doorn S, Reinecke M, Kuster B, van Bergen en Henegouwen P, et al. Adaptive resistance to EGFR-targeted therapy by calcium signaling in NSCLC cells. Mol Cancer Res. 2018;16:1773–84. [DOI] [PubMed]

94.

Chanda K, Jana NR, Mukhopadhyay D. Long non-coding RNA MALAT1 protects against Aβ_1–42 induced toxicity by regulating the expression of receptor tyrosine kinase EPHA2 via quenching miR-200a/26a/26b in Alzheimer’s disease. Life Sci. 2022;302:120652. [DOI] [PubMed]

95.

Borroto-Escuela DO, Ambrogini P, Narvaez M, Di Liberto V, Beggiato S, Ferraro L, et al. Serotonin heteroreceptor complexes and their integration of signals in neurons and astroglia—relevance for mental diseases. Cells. 2021;10:1902. [DOI] [PubMed] [PMC]

96.

Narváez M, Andrade-Talavera Y, Valladolid-Acebes I, Fredriksson M, Siegele P, Hernandez-Sosa A, et al. Existence of FGFR1-5-HT1AR heteroreceptor complexes in hippocampal astrocytes. Putative link to 5-HT and FGF2 modulation of hippocampal gamma oscillations. Neuropharmacology. 2020;170:108070. [DOI] [PubMed]

97.

Heimfarth L, da Silva Ferreira F, Pierozan P, Loureiro SO, Mingori MR, Moreira JCF, et al. Calcium signaling mechanisms disrupt the cytoskeleton of primary astrocytes and neurons exposed to diphenylditelluride. Biochim Biophys Acta. 2016;1860:2510–20. [DOI] [PubMed]

98.

Stork T, Sheehan A, Tasdemir-Yilmaz OE, Freeman MR. Neuron-glia interactions through the Heartless FGF receptor signaling pathway mediate morphogenesis of Drosophila astrocytes. Neuron. 2014;83:388–403. [DOI] [PubMed] [PMC]

99.

Pathak D, Sriram K. Neuron-astrocyte omnidirectional signaling in neurological health and disease. Front Mol Neurosci. 2023;16:1169320. [DOI] [PubMed] [PMC]

100.

Santiago-Mujika E, Luthi-Carter R, Giorgini F, Kalaria RN, Mukaetova-Ladinska EB. Tubulin and tubulin posttranslational modifications in Alzheimer’s disease and vascular dementia. Front Aging Neurosci. 2021;13:730107. [DOI] [PubMed] [PMC]

101.

Chanda K, Jana NR, Mukhopadhyay D. Receptor tyrosine kinase ROR1 ameliorates Aβ_1–42 induced cytoskeletal instability and is regulated by the miR146a-NEAT1 nexus in Alzheimer’s disease. Sci Rep. 2021;11:19254. [DOI] [PubMed] [PMC]

102.

Zhou R, Han B, Xia C, Zhuang X. Membrane-associated periodic skeleton is a signaling platform for RTK transactivation in neurons. Science. 2019;365:929–34. [DOI] [PubMed] [PMC]

103.

Sowa G. Caveolae, caveolins, cavins, and endothelial cell function: new insights. Front Physiol. 2012;2:120. [DOI] [PubMed] [PMC]

104.

Head BP, Patel HH, Insel PA. Interaction of membrane/lipid rafts with the cytoskeleton: Impact on signaling and function: membrane/lipid rafts, mediators of cytoskeletal arrangement and cell signaling. Biochim Biophys Acta. 2014;1838:532–45. [DOI] [PubMed] [PMC]

105.

Deneka A, Korobeynikov V, Golemis EA. Embryonal Fyn-associated substrate (EFS) and CASS4: the lesser-known CAS protein family members. Gene. 2015;570:25–35. [DOI] [PubMed] [PMC]

106.

Beck TN, Nicolas E, Kopp MC, Golemis EA. Adaptors for disorders of the brain? The cancer signaling proteins NEDD9, CASS4, and PTK2B in Alzheimer’s disease. Oncoscience. 2014;1:486–503. [DOI] [PubMed] [PMC]

107.

Perruche S, Saas P. L14. Immunomodulatory properties of apoptotic cells. Presse Med. 2013;42:537–43. [DOI] [PubMed]

108.

Mills JC, Stone NL, Pittman RN. Extranuclear apoptosis: the role of the cytoplasm in the execution phase. J Cell Biol. 1999;146:703–8. [DOI] [PubMed] [PMC]

109.

Yoshii S, Tanaka M, Otsuki Y, Wang DY, Guo RJ, Zhu Y, et al. αPIX nucleotide exchange factor is activated by interaction with phosphatidylinositol 3-kinase. Oncogene. 1999;18:5680–90. [DOI] [PubMed]

110.

Kwon Y, Jeon YW, Kwon M, Cho Y, Park D, Shin JE. βPix-d promotes tubulin acetylation and neurite outgrowth through a PAK/stathmin1 signaling pathway. PLoS One. 2020;15:e0230814. Erratum in: PLoS One. 2020;15:e0233327. [DOI] [PubMed] [PMC]

111.

Taya S, Inagaki N, Sengiku H, Makino H, Iwamatsu A, Urakawa I, et al. Direct interaction of insulin-like growth factor-1 receptor with leukemia-associated RhoGEF. J Cell Biol. 2001;155:809–20. [DOI] [PubMed] [PMC]

112.

Stankiewicz TR, Linseman DA. Rho family GTPases: key players in neuronal development, neuronal survival, and neurodegeneration. Front Cell Neurosci. 2014;8:314. [DOI] [PubMed] [PMC]

113.

Kanehisa M, Furumichi M, Sato Y, Kawashima M, Ishiguro-Watanabe M. KEGG for taxonomy-based analysis of pathways and genomes. Nucleic Acids Res. 2023;51:D587–92. [DOI] [PubMed] [PMC]

114.

Mattson MP, Magnus T. Ageing and neuronal vulnerability. Nat Rev Neurosci. 2006;7:278–94. [DOI] [PubMed] [PMC]

115.

Wang D, Chen F, Han Z, Yin Z, Ge X, Lei P. Relationship between amyloid-β deposition and blood–brain barrier dysfunction in Alzheimer’s disease. Front Cell Neurosci. 2021;15:695479. [DOI] [PubMed] [PMC]

116.

Bolognin S, Lorenzetto E, Diana G, Buffelli M. The potential role of rho GTPases in Alzheimer’s disease pathogenesis. Mol Neurobiol. 2014;50:406–22. [DOI] [PubMed]

117.

Cheng KC, Chen YH, Wu CL, Lee WP, Cheung CHA, Chiang HC. Rac1 and Akt exhibit distinct roles in mediating Aβ-induced memory damage and learning impairment. Mol Neurobiol. 2021;58:5224–38. [DOI] [PubMed]

118.

Zhang H, Ben Zablah Y, Zhang H, Jia Z. Rho signaling in synaptic plasticity, memory, and brain disorders. Front Cell Dev Biol. 2021;9:729076. [DOI] [PubMed] [PMC]

119.

Rong Z, Cheng B, Zhong L, Ye X, Li X, Jia L, et al. Activation of FAK/Rac1/Cdc42-GTPase signaling ameliorates impaired microglial migration response to Aβ₄₂ in triggering receptor expressed on myeloid cells 2 loss-of-function murine models. FASEB J. 2020;34:10984–97. [DOI] [PubMed]

120.

Huesa G, Baltrons MA, Gómez-Ramos P, Morán A, García A, Hidalgo J, et al. Altered distribution of RhoA in Alzheimer’s disease and AβPP overexpressing mice. J Alzheimers Dis. 2010;19:37–56. [DOI] [PubMed]

121.

Pianu B, Lefort R, Thuiliere L, Tabourier E, Bartolini F. The Aβ₁₋₄₂ peptide regulates microtubule stability independently of tau. J Cell Sci. 2014;127:1117–27. [DOI] [PubMed]

122.

Richter M, Murtaza N, Scharrenberg R, White SH, Johanns O, Walker S, et al. Altered TAOK2 activity causes autism-related neurodevelopmental and cognitive abnormalities through RhoA signaling. Mol Psychiatry. 2019;24:1329–50. [DOI] [PubMed] [PMC]

123.

Jarosz-Griffiths HH, Noble E, Rushworth JV, Hooper NM. Amyloid-β receptors: the good, the bad, and the prion protein. J Biol Chem. 2016;291:3174–83. [DOI] [PubMed] [PMC]

124.

Pottier C, Fresnais M, Gilon M, Jérusalem G, Longuespée R, Sounni NE. Tyrosine kinase inhibitors in cancer: breakthrough and challenges of targeted therapy. Cancers (Basel). 2020;12:731. [DOI] [PubMed] [PMC]

125.

Hamid O, Cowey CL, Offner M, Faries M, Carvajal RD. Efficacy, safety, and tolerability of approved combination BRAF and MEK inhibitor regimens for BRAF-mutant melanoma. Cancers (Basel). 2019;11:1642. [DOI] [PubMed] [PMC]

126.

Zhang X, Song S, Peng W. Cell cycle deregulation in neurodegenerative diseases. Int J Neurosci. 2023;133:408–16. [DOI] [PubMed]

127.

Martínez-Cué C, Rueda N. Cellular senescence in neurodegenerative diseases. Front Cell Neurosci. 2020;14:16. [DOI] [PubMed] [PMC]

128.

Joseph C, Mangani AS, Gupta V, Chitranshi N, Shen T, Dheer Y, et al. Cell cycle deficits in neurodegenerative disorders: uncovering molecular mechanisms to drive innovative therapeutic development. Aging Dis. 2020;11:946–66. [DOI] [PubMed] [PMC]

129.

Sengupta P, Mukhopadhyay D. Possibilities of combinatorial therapy: insulin dysregulation and the growth hormone perspective on neurodegeneration. In: Khalil IA, editor. Pharmacogenetics. Rijeka: IntechOpen; 2021.

130.

Li L, Zhu M, Wu W, Qin B, Gu J, Tu Y, et al. Brivanib, a multitargeted small‐molecule tyrosine kinase inhibitor, suppresses laser‐induced CNV in a mouse model of neovascular AMD. J Cell Physiol. 2020;235:1259–73. [DOI] [PubMed]

131.

Inana G, Murat C, An W, Yao X, Harris IR, Cao J. RPE phagocytic function declines in age-related macular degeneration and is rescued by human umbilical tissue derived cells. J Transl Med. 2018;16:63. [DOI] [PubMed] [PMC]

132.

Kitahara H, Kajikawa S, Ishii Y, Yamamoto S, Hamashima T, Azuma E, et al. The novel pathogenesis of retinopathy mediated by multiple RTK signals is uncovered in newly developed mouse model. EBioMedicine. 2018;31:190–201. [DOI] [PubMed] [PMC]

133.

Tavassoly O, Sato T, Tavassoly I. Inhibition of brain epidermal growth factor receptor activation: a novel target in neurodegenerative diseases and brain injuries. Mol Pharmacol. 2020;98:13–22. [DOI] [PubMed]

134.

Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 2007;316:1039–43. [DOI] [PubMed]

135.

Aguilar BJ, Zhu Y, Lu Q. Rho GTPases as therapeutic targets in Alzheimer’s disease. Alzheimers Res Ther. 2017;9:97. [DOI] [PubMed] [PMC]

136.

Désiré L, Bourdin J, Loiseau N, Peillon H, Picard V, de Oliveira C, et al. RAC1 inhibition targets amyloid precursor protein processing by γ-secretase and decreases Aβ production in vitro and in vivo. J Biol Chem. 2005;280:37516–25. [DOI] [PubMed]

137.

Manterola L, Hernando-Rodríguez M, Ruiz A, Apraiz A, Arrizabalaga O, Vellón L, et al. 1–42 β-Amyloid peptide requires PDK1/nPKC/Rac 1 pathway to induce neuronal death. Transl Psychiatry. 2013;3:e219. [DOI] [PubMed] [PMC]

138.

Leuchtenberger S, Kummer MP, Kukar T, Czirr E, Teusch N, Sagi SA, et al. Inhibitors of Rho-kinase modulate amyloid-beta (Aβ) secretion but lack selectivity for Aβ42. J Neurochem. 2006;96:355–65. [DOI] [PubMed]

139.

Herskowitz JH, Feng Y, Mattheyses AL, Hales C, Higginbotham LA, Duong D, et al. Pharmacologic inhibition of ROCK2 suppresses amyloid-β production in an Alzheimer’s disease mouse model. J Neurosci. 2013;33:19086–98. [DOI] [PubMed] [PMC]

140.

Zhou Y, Su Y, Li B, Liu F, Ryder JW, Wu X, et al. Nonsteroidal anti-inflammatory drugs can lower amyloidogenic Aβ₄₂ by inhibiting Rho. Science. 2003;302:1215–7. [DOI] [PubMed]

141.

Ouyang ZH, Wang WJ, Yan YG, Wang B, Lv GH. The PI3K/Akt pathway: a critical player in intervertebral disc degeneration. Oncotarget. 2017;8:57870–81. [DOI] [PubMed] [PMC]

142.

Sasore T, Reynolds AL, Kennedy BN. Targeting the PI3K/Akt/mTOR pathway in ocular neovascularization. In: Ash JD, Grimm C, Hollyfield JG, editors. Retinal degenerative diseases. New York: Springer; 2014. pp. 805–11. [DOI] [PubMed]

143.

Hausott B, Park JW, Valovka T, Offterdinger M, Hess MW, Geley S, et al. Subcellular localization of Sprouty2 in human glioma cells. Front Mol Neurosci. 2019;12:73. [DOI] [PubMed] [PMC]

144.

Hausott B, Klimaschewski L. Sprouty2—a novel therapeutic target in the nervous system? Mol Neurobiol. 2019;56:3897–903. [DOI] [PubMed] [PMC]

145.

Brandt R, Götz J. Special issue on “Cytoskeletal proteins in health and neurodegenerative disease: concepts and methods”. Brain Res Bull. 2023;198:50–2. [DOI] [PubMed]