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RTK Signaling

Written/Edited by Dr. Stefan Pellenz, PhD

Receptor Tyrosine Kinases (RTKs) are membrane bound kinases that are activated upon binding of receptor specific ligands. They make up the largest class of membrane receptors that trigger signaling cascades through their inherent enzymatic activity. These structures, activation mechanisms and key components of the signaling pathways are highly conserved in metazoans. The RTK family includes, epidermal growth factor receptors (EGFR), platelet-derived growth factor receptors (PDGFR), fibroblast growth factor receptors (FGFR), vascular endothelial growth factor receptors (VEGFR), the insulin receptor, and many more. There are in total 58 known RTKs in humans, which are grouped into 20 classes depending on topology.

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RTKs are fairly promiscuous receptors, and activating stimuli comprise a plethora of growth factors, hormones, and cytokines. Most RTKs form dimers and become active upon ligand binding. The active RTK phosphorylates activators of downstream signaling cascades such as NF-kB, MAPK, Ca2+ dependent signaling, and the JAK-STAT pathway.

RTKs affect a wide spectrum of processes ranging from cytoskeleton dynamics, cell growth and differentiation to inflammation, apoptosis, and tumor progression. In spite of the exceptionally high variety of receptors and outcomes, RTKs engage only a limited set of core processes. Therefore, quantitative analysis of factors like an RTK’s expression profile are crucial for the understanding of the signaling processes and predicting qualitative outcomes.

Dysregulated RTK signaling, often triggered by overexpression or mutation of RTKs like insulin receptor (IR) or fibroblast growth factor receptor (FGFR), contributes to metabolic imbalances, including impaired insulin sensitivity and adipogenesis. These disruptions promote excessive fat accumulation and chronic inflammation, hallmark features of obesity, while also influencing energy homeostasis by altering pathways like PI3K-AKT and MAPK signaling. Moreover, RTK-mediated cross-talk with other signaling networks, such as leptin and mTOR pathways, exacerbates the metabolic derangements observed in obesity, making RTKs a critical target for understanding and mitigating this condition.

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Related Pathways

References:

Bromann, Korkaya, Courtneidge: "The interplay between Src family kinases and receptor tyrosine kinases." in: Oncogene, Vol. 23, Issue 48, pp. 7957-68, (2004) (PubMed).
Anguita, Villalobo: "Ca2+ signaling and Src-kinases-controlled cellular functions." in: Archives of biochemistry and biophysics, Vol. 650, pp. 59-74, (2019) (PubMed).
Anguita, Villalobo: "Src-family tyrosine kinases and the Ca2+ signal." in: Biochimica et biophysica acta. Molecular cell research, Vol. 1864, Issue 6, pp. 915-932, (2017) (PubMed).
Lemmon, Schlessinger: "Cell signaling by receptor tyrosine kinases." in: Cell, Vol. 141, Issue 7, pp. 1117-34, (2010) (PubMed).
Sudhesh Dev, Zainal Abidin, Farghadani, Othman, Naidu: "Receptor Tyrosine Kinases and Their Signaling Pathways as Therapeutic Targets of Curcumin in Cancer." in: Frontiers in pharmacology, Vol. 12, pp. 772510, (2021) (PubMed).
Kashiwada, Lu, Rothman: "PIP3 pathway in regulatory T cells and autoimmunity." in: Immunologic research, Vol. 39, Issue 1-3, pp. 194-224, (2008) (PubMed).
Putney, Tomita: "Phospholipase C signaling and calcium influx." in: Advances in biological regulation, Vol. 52, Issue 1, pp. 152-64, (2013) (PubMed).
Margolis, Bellot, Honegger, Ullrich, Schlessinger, Zilberstein: "Tyrosine kinase activity is essential for the association of phospholipase C-gamma with the epidermal growth factor receptor." in: Molecular and cellular biology, Vol. 10, Issue 2, pp. 435-41, (1990) (PubMed).
Schlessinger, Lemmon: "SH2 and PTB domains in tyrosine kinase signaling." in: Science's STKE : signal transduction knowledge environment, Vol. 2003, Issue 191, pp. RE12, (2003) (PubMed).
Wagner, Stacey, Liu, Pawson: "Molecular mechanisms of SH2- and PTB-domain-containing proteins in receptor tyrosine kinase signaling." in: Cold Spring Harbor perspectives in biology, Vol. 5, Issue 12, pp. a008987, (2014) (PubMed).
Duan, Chen, Virmani, Ying, Raja, Chung, Rainey, Dimri, Ortega-Cava, Zhao, Clubb, Tu, Reddi, Naramura, Band, Band: "Distinct roles for Rho versus Rac/Cdc42 GTPases downstream of Vav2 in regulating mammary epithelial acinar architecture." in: The Journal of biological chemistry, Vol. 285, Issue 2, pp. 1555-68, (2010) (PubMed).
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Ligand

ANGPT1 - Angiopoietin 1:

ANGPT2 - Angiopoietin 2:

BDNF (Brain-Derived Neurotrophic Factor):

Figf - VEGFD:

COL11A2 (Collagen, Type XI, alpha 2):

EGF (Epidermal Growth Factor):

FGF6 (Fibroblast Growth Factor 6):

FGF7 (Fibroblast Growth Factor 7):

GDNF (Glial Cell Line Derived Neurotrophic Factor):

LGALS3 - Galectin 3:

MDK - Midkine:

NGFB (Nerve Growth Factor beta):

PDGFD (Platelet Derived Growth Factor D):

TUB (Tubby Homolog):

ATF2 (Activating Transcription Factor 2):

AREG - Amphiregulin:

ANGPT4 - Angiopoietin 4:

BTC - Betacellulin:

CSF1 - M-CSF/CSF1:

EFNA1 - Ephrin A1:

EFNA3 - Ephrin A3:

EFNA4 (Ephrin A4):

EFNA5 - Ephrin A5:

EFNB1 - Ephrin B1:

EFNB2 - Ephrin B2:

EFNB3 - Ephrin B3:

EREG - Epiregulin:

EPGN - Epigen:

FGF1 (Fibroblast Growth Factor 1 (Acidic)):

FGF10 (Fibroblast Growth Factor 10):

FGF19 (Fibroblast Growth Factor 19):

FGF2 (Fibroblast Growth Factor 2 (Basic)):

FGF21 (Fibroblast Growth Factor 21):

FGF22 (Fibroblast Growth Factor 22):

FGF23 (Fibroblast Growth Factor 23):

FGF3 (Fibroblast Growth Factor 3):

FGF4 (Fibroblast Growth Factor 4):

FGF5 (Fibroblast Growth Factor 5):

FGF8 (Fibroblast Growth Factor 8 (Androgen-Induced)):

FLT3LG (Fms-Related tyrosine Kinase 3 Ligand):

GDNF (Glial Cell Line Derived Neurotrophic Factor):

GAS6 (Growth Arrest-Specific 6):

HBEGF (Heparin-Binding EGF-Like Growth Factor):

HGF (Hepatocyte Growth Factor (Hepapoietin A, Scatter Factor)):

INS - Insulin:

IGF1 (Insulin-Like Growth Factor 1):

IL34 - IL-34:

KITLG - KIT Ligand:

NRG1 - Neuregulin 1:

NRG2 - Neuregulin 2:

NRG3 - Neuregulin 3:

NRG4 - Neuregulin 4:

NTF3 - Neurotrophin 3:

NTF4 - Neurotrophin 4:

PDGFB (Platelet Derived Growth Factor Subunit B):

PDGFA (Platelet Derived Growth Factor A):

PDGFC (Platelet-Derived Growth Factor C):

PTN - Pleiotrophin:

TGFA (Transforming Growth Factor, alpha):

TULP1 (Tubby Like Protein 1):

VEGFA (Vascular Endothelial Growth Factor A):

VEGFB (Vascular Endothelial Growth Factor B):

VEGFC (Vascular Endothelial Growth Factor C):

RTK

TYRO3 (TYRO3 Protein Tyrosine Kinase):

AATK (Apoptosis-Associated tyrosine Kinase):

AXL (AXL Receptor tyrosine Kinase):

MERTK (C-Mer Proto-Oncogene Tyrosine Kinase):

EPHA3 - EPH Receptor A3:

EPHA4 - EPH Receptor A4:

EPHA5 - EPH Receptor A5:

Epha6 - EPH Receptor A6:

EPHA8 - EPH Receptor A8:

FGFR1 (Fibroblast Growth Factor Receptor 1):

FGFR2 (Fibroblast Growth Factor Receptor 2):

INSR - Insulin Receptor:

MST1R (Macrophage Stimulating 1 Receptor (C-Met-Related tyrosine Kinase)):

NTRK1 - TRKA:

NTRK2 - TRKB:

KIT (Mast/stem Cell Growth Factor Receptor):

ALK (Anaplastic Lymphoma Receptor tyrosine Kinase):

ALK Antibodies

ROS1 (C-Ros Oncogene 1 , Receptor tyrosine Kinase):

CSF1R (Colony Stimulating Factor 1 Receptor):

DDR1 (Discoidin Domain Receptor tyrosine Kinase 1):

DDR2 (Discoidin Domain Receptor tyrosine Kinase 2):

EPHA10 - EPH Receptor A10:

EPHA2 - EPH Receptor A2:

EPHA7 - EPH Receptor A7:

EPHB1 - EPH Receptor B1:

EPHB2 - EPH Receptor B2:

EPHB3 - EPH Receptor B3:

EPHB4 - EPH Receptor B4:

EPHB6 - EPH Receptor B6:

EGFR (Epidermal Growth Factor Receptor):

FGFR3 (Fibroblast Growth Factor Receptor 3):

FGFR4 (Fibroblast Growth Factor Receptor 4):

FGFRL1 (Fibroblast Growth Factor Receptor-Like 1):

FLT1 (Fms-Related tyrosine Kinase 1 (VEGFR1)):

FLT3 (Fms-Related tyrosine Kinase 3):

FLT4 (Fms-Related Tyrosine Kinase 4):

INSRR (Insulin Receptor-Related Receptor):

IGF1R (Insulin-Like Growth Factor 1 Receptor):

VEGFR2 - VEGFR2/CD309:

LMTK2 (Lemur tyrosine Kinase 2):

LTK (Leukocyte Receptor tyrosine Kinase):

KIT (Mast/stem Cell Growth Factor Receptor):

MME (Membrane Metallo-Endopeptidase):

MET - c-MET:

MUSK (Muscle, Skeletal, Receptor Tyrosine Kinase):

NTRK3 (Neurotrophic tyrosine Kinase, Receptor, Type 3):

PDGFRA (Platelet Derived Growth Factor Receptor alpha):

KCNH8 (Potassium Voltage-Gated Channel, Subfamily H (Eag-Related), Member 8):

PTK7 (PTK7 Protein tyrosine Kinase 7):

ROR1 (Receptor Tyrosine Kinase-Like Orphan Receptor 1):

ROR2 (Receptor Tyrosine Kinase-Like Orphan Receptor 2):

RET - Ret Proto-Oncogene:

RYK (RYK Receptor-Like Tyrosine Kinase):

TEK (TEK Tyrosine Kinase, Endothelial):

TIE1 (tyrosine Kinase with Immunoglobulin-Like and EGF-Like Domains 1):

ERBB4 (V-Erb-A erythroblastic Leukemia Viral Oncogene Homolog 4 (Avian)):

ErbB2/Her2 (Receptor tyrosine-protein kinase erbB-2):

ERBB3 (Receptor Tyrosine-Protein Kinase ErbB-3):

Adaptors

SHC1 (SHC (Src Homology 2 Domain Containing) Transforming Protein 1):

SHC2 (SHC (Src Homology 2 Domain Containing) Transforming Protein 2):

GAB1 (GRB2-Associated Binding Protein 1):

GAB1 Antibodies

GRB2 (Growth Factor Receptor-Bound Protein 2):

SHC3 (SHC (Src Homology 2 Domain Containing) Transforming Protein 3):

GEF

RASGRF1 (Ras Protein-Specific Guanine Nucleotide-Releasing Factor 1):

SOS1 (Son of Sevenless Homolog 1):

RAPGEF5 - GFR:

SOS2 (Son of Sevenless Homolog 2):

GTPase

RHOG (Ras Homolog Family Member G):

RAC2 (Ras-Related C3 Botulinum Toxin Substrate 2 (Rho Family, Small GTP Binding Protein Rac2)):

CDC42 (Cell Division Cycle 42 (GTP Binding Protein, 25kDa)):

NRAS - GTPase NRas:

HRAS (HRas proto-oncogene, GTPase):

RAC3 (Ras-Related C3 Botulinum Toxin Substrate 3 (Rho Family, Small GTP Binding Protein Rac3)):

Inhibitor

DEPTOR (DEP Domain Containing mTOR-Interacting Protein):

TSC1 (Tuberous Sclerosis 1):

TSC2 - Tuberin:

Kinase

MAPK1 - ERK2:

MAPK3 - ERK1:

PAK1 (P21-Activated Kinase 1):

PAK2 (P21-Activated Kinase 2):

PAK4 (P21-Activated Kinase 4):

AKT1 (V-Akt Murine Thymoma Viral Oncogene Homolog 1):

AKT2 (V-Akt Murine Thymoma Viral Oncogene Homolog 2):

AKT3 (V-Akt Murine Thymoma Viral Oncogene Homolog 3 (Protein Kinase B, Gamma)):

mTOR - MTOR:

MAP2K1 - MEK1:

MAP2K2 - MEK2:

PIK3CA (Phosphoinositide-3-Kinase, Catalytic, alpha Polypeptide):

PIK3CG - PIK3 gamma:

PRKCZ - PKC zeta:

PDK1 (Pyruvate Dehydrogenase Kinase 1):

PDK2 (Pyruvate Dehydrogenase Kinase, Isozyme 2):

RPS6KB1 (Ribosomal Protein S6 Kinase, 70kDa, Polypeptide 1):

RPS6KB2 (Ribosomal Protein S6 Kinase, 70kDa, Polypeptide 2):

Messenger

Calm2 - Calmodulin 2:

CALM3 - Calmodulin 3:

Phosphatase

PPP3CA (Protein Phosphatase 3, Catalytic Subunit, alpha Isoform):

PTPN11 (Protein tyrosine Phosphatase, Non-Receptor Type 11):

PPP3CB (Protein Phosphatase 3, Catalytic Subunit, beta Isozyme):

PPP3CC (Protein Phosphatase 3, Catalytic Subunit, gamma Isozyme):

PPP3R1 (Protein Phosphatase 3, Regulatory Subunit B, alpha):

Phospholipase

PLCG2 - Phospholipase C gamma 2:

PLCG1 - Phospholipase C gamma 1:

PLD2 - Phospholipase D2:

Pro-apoptotic

BAD (BCL2-Associated Agonist of Cell Death):

Protease

CASP9 - Caspase 9:

Protein kinase

IKBKB (Inhibitor of kappa Light Polypeptide Gene Enhancer in B-Cells, Kinase beta):

JAK1 (Janus Kinase 1):

JAK2 (Janus Kinase 2):

CHUK - IKK alpha:

IKBKG (Inhibitor of kappa Light Polypeptide Gene Enhancer in B-Cells, Kinase gamma):

JAK3 (Janus Kinase 3):

ARAF (V-Raf Murine Sarcoma 3611 Viral Oncogene Homolog):

BRAF (B-Raf proto-oncogene, serine/threonine kinase):

RAF1 (V-Raf-1 Murine Leukemia Viral Oncogene Homolog 1):

Regulator

EIF4EBP1 - eIF4EBP1:

GBL (G protein beta subunit-like):

RHEB (Ras Homolog Enriched in Brain):

Transcription factor

JUN - C-JUN:

NFATC1 (Nuclear Factor of Activated T-Cells, Cytoplasmic, Calcineurin-Dependent 1):

NFkBP65 - NF-kB p65:

STAT1 (Signal Transducer and Activator of Transcription 1, 91kDa):

STAT3 (Signal Transducer and Activator of Transcription 3 (Acute-Phase Response Factor)):

NFAT5 (Nuclear Factor of Activated T-Cells 5, Tonicity-Responsive):

NFAT1 (Nuclear Factor of Activated T-Cells, Cytoplasmic, Calcineurin-Dependent 2):

NFATC3 (Nuclear Factor of Activated T-Cells, Cytoplasmic, Calcineurin-Dependent 3):

NFATC4 (Nuclear Factor of Activated T-Cells, Cytoplasmic, Calcineurin-Dependent 4):