RCP-driven α5β1 recycling suppresses Rac and promotes RhoA activity via the RacGAP1–IQGAP1 complex

Inhibition of αvβ3 or expression of mutant p53 promotes invasion into fibronectin (FN)-containing extracellular matrix (ECM) by enhancing Rab-coupling protein (RCP)–dependent recycling of α5β1 integrin. RCP and α5β1 cooperatively recruit receptor tyrosine kinases, including EGFR1, to regulate their trafficking and downstream signaling via protein kinase B (PKB)/Akt, which, in turn, promotes invasive migration. In this paper, we identify a novel PKB/Akt substrate, RacGAP1, which is phosphorylated as a consequence of RCP-dependent α5β1 trafficking. Phosphorylation of RacGAP1 promotes its recruitment to IQGAP1 at the tips of invasive pseudopods, and RacGAP1 then locally suppresses the activity of the cytoskeletal regulator Rac and promotes the activity of RhoA in this subcellular region. This Rac to RhoA switch promotes the extension of pseudopodial processes and invasive migration into FN-containing matrices, in a RhoA-dependent manner. Thus, the localized endocytic trafficking of α5β1 within the tips of invasive pseudopods elicits signals that promote the reorganization of the actin cytoskeleton, protrusion, and invasion into FN-rich ECM.

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SHCA PHOSPHOTYROSINE DERIVED SIGNALING IS REQUIRED FOR THE MAINTENANCE OF CARDIAC FUNCTION

Clinical & Investigative Medicine ◽

10.25011/cim.v31i4.4829 ◽

2008 ◽

Vol 31 (4) ◽

pp. 23

Author(s):

Rachel Vanderlaan ◽

Rod Hardy ◽

Golam Kabir ◽

Peter Back ◽

A J Pawson

Keyword(s):

Extracellular Matrix ◽

Cardiac Function ◽

Tyrosine Kinases ◽

Sh2 Domain ◽

Scaffolding Protein ◽

Restricted Domain ◽

Downstream Signaling ◽

Matrix Interactions ◽

Extracellular Matrix Interactions ◽

Ptb Domain

Background: ShcA, a scaffolding protein, generates signalspecificity by docking to activated tyrosine kinases through distinct phosphotyrosine recognition motifs, while mediating signal complexity through formation of diverse downstream phosphotyrosine complexes. Mammalian ShcA encodes 3 isoforms having a modular architecture of a PTB domain and SH2 domain, separated by a CH1 region containing tyrosine phosphorylation sites important in Ras-MAPK activation. Objective and Methods: ShcA has a necessary role in cardiovascular development^1,2. However, the role of ShcA in the adult myocardium is largely unknown, also unclear, is how ShcA uses its signaling modules to mediate downstream signaling. To this end, cre/loxP technology was employed to generate a conditional ShcA allele series. The myocardial specific ShcA KO (ShcA CKO) and myocardial restricted domain mutant KI mice were generated using cre expressed from the mlc2v locus^3 coupled with the ShcA floxed allele and in combination with the individual ShcA domain mutant KI alleles^2. Results: ShcACKO mice develop a dilated cardiomyopathy phenotype by 3 months of life, typified by depressed cardiac function and enlarged chamber dimensions. Isolated cardiomyocytes from ShcA CKO mice have preserved contractility indicating an uncoupling between global heart function and single myocyte contractile mechanics. Force-length experiments suggest that the loss of shcAmediates the uncoupling through deregulation of extracellular matrix interactions. Subsequent, analysis of the ShcA myocardial restricted domain mutant KImice suggests that ShcA requires PTB domain docking to upstream tyrosine kinases and subsequent phosphorylation of the CH1 tyrosines important for downstream signaling. Conclusion: ShcA is required for proper maintenance of cardiac function, possibly regulation of extracellular matrix interactions. References: 1. Lai KV, Pawson AJ. The ShcA phosphotyrosine docking protein sensitizescardiovascular signaling in the mouse embryo. Genes and Dev 2000;14:1132-45. 2. Hardy WR. et al. Combinatorial ShcA docking interactions supportdiversity in tissue morphogenesis. Science2007;317:251-6. 3.Minamisawa, s. et al. A post-transcriptional compensatory pathway inheterozygous ventricular myosin light chain 2-deficient mice results in lack ofgene dosage effect during normal cardiac growth or hypertrophy. J Biol Chem 1999;274:10066-70.

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Receptor Tyrosine Kinases in Kidney Development

Journal of Signal Transduction ◽

10.1155/2011/869281 ◽

2011 ◽

Vol 2011 ◽

pp. 1-10 ◽

Cited By ~ 14

Author(s):

Renfang Song ◽

Samir S. El-Dahr ◽

Ihor V. Yosypiv

Keyword(s):

Tyrosine Kinases ◽

Molecular Mechanisms ◽

Kidney Development ◽

Receptor Tyrosine Kinases ◽

Adaptor Proteins ◽

Downstream Signaling ◽

Arterial Blood ◽

Intracellular Signal ◽

Human Birth

The kidney plays a fundamental role in the regulation of arterial blood pressure and fluid/electrolyte homeostasis. As congenital anomalies of the kidney and urinary tract (CAKUT) constitute one of the most common human birth defects, improved understanding of the cellular and molecular mechanisms that lead to CAKUT is critical. Accumulating evidence indicates that aberrant signaling via receptor tyrosine kinases (RTKs) is causally linked to CAKUT. Upon activation by their ligands, RTKs dimerize, undergo autophosphorylation on specific tyrosine residues, and interact with adaptor proteins to activate intracellular signal transduction pathways that regulate diverse cell behaviours such as cell proliferation, survival, and movement. Here, we review the current understanding of role of RTKs and their downstream signaling pathways in the pathogenesis of CAKUT.

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Receptor Tyrosine Kinases and Their Signaling Pathways as Therapeutic Targets of Curcumin in Cancer

Frontiers in Pharmacology ◽

10.3389/fphar.2021.772510 ◽

2021 ◽

Vol 12 ◽

Author(s):

Sareshma Sudhesh Dev ◽

Syafiq Asnawi Zainal Abidin ◽

Reyhaneh Farghadani ◽

Iekhsan Othman ◽

Rakesh Naidu

Keyword(s):

Signaling Pathways ◽

Cancer Progression ◽

Tyrosine Kinases ◽

Receptor Tyrosine Kinases ◽

Surface Proteins ◽

Downstream Signaling ◽

Anti Cancer ◽

Rtk Inhibitors

Receptor tyrosine kinases (RTKs) are transmembrane cell-surface proteins that act as signal transducers. They regulate essential cellular processes like proliferation, apoptosis, differentiation and metabolism. RTK alteration occurs in a broad spectrum of cancers, emphasising its crucial role in cancer progression and as a suitable therapeutic target. The use of small molecule RTK inhibitors however, has been crippled by the emergence of resistance, highlighting the need for a pleiotropic anti-cancer agent that can replace or be used in combination with existing pharmacological agents to enhance treatment efficacy. Curcumin is an attractive therapeutic agent mainly due to its potent anti-cancer effects, extensive range of targets and minimal toxicity. Out of the numerous documented targets of curcumin, RTKs appear to be one of the main nodes of curcumin-mediated inhibition. Many studies have found that curcumin influences RTK activation and their downstream signaling pathways resulting in increased apoptosis, decreased proliferation and decreased migration in cancer both in vitro and in vivo. This review focused on how curcumin exhibits anti-cancer effects through inhibition of RTKs and downstream signaling pathways like the MAPK, PI3K/Akt, JAK/STAT, and NF-κB pathways. Combination studies of curcumin and RTK inhibitors were also analysed with emphasis on their common molecular targets.

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SRC Kinase in Glioblastoma: News from an Old Acquaintance

Cancers ◽

10.3390/cancers12061558 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1558 ◽

Cited By ~ 1

Author(s):

Claudia Cirotti ◽

Claudia Contadini ◽

Daniela Barilà

Keyword(s):

Receptor Tyrosine Kinase ◽

Tyrosine Kinases ◽

Receptor Tyrosine Kinases ◽

Metabolic Reprogramming ◽

Constitutive Activity ◽

Therapeutic Approaches ◽

Resistance To Therapy ◽

Downstream Signaling ◽

Wide Range ◽

Therapy Effectiveness

Glioblastoma multiforme (GBM) is one of the most recalcitrant brain tumors characterized by a tumor microenvironment (TME) that strongly supports GBM growth, aggressiveness, invasiveness, and resistance to therapy. Importantly, a common feature of GBM is the aberrant activation of receptor tyrosine kinases (RTKs) and of their downstream signaling cascade, including the non-receptor tyrosine kinase SRC. SRC is a central downstream intermediate of many RTKs, which triggers the phosphorylation of many substrates, therefore, promoting the regulation of a wide range of different pathways involved in cell survival, adhesion, proliferation, motility, and angiogenesis. In addition to the aforementioned pathways, SRC constitutive activity promotes and sustains inflammation and metabolic reprogramming concurring with TME development, therefore, actively sustaining tumor growth. Here, we aim to provide an updated picture of the molecular pathways that link SRC to these events in GBM. In addition, SRC targeting strategies are discussed in order to highlight strengths and weaknesses of SRC inhibitors in GBM management, focusing our attention on their potentialities in combination with conventional therapeutic approaches (i.e., temozolomide) to ameliorate therapy effectiveness.

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Functional Profiling of Receptor Tyrosine Kinases and Downstream Signaling in Human Chondrosarcomas Identifies Pathways for Rational Targeted Therapy

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-12-3647 ◽

2013 ◽

Vol 19 (14) ◽

pp. 3796-3807 ◽

Cited By ~ 45

Author(s):

Yi-Xiang Zhang ◽

Jolieke G. van Oosterwijk ◽

Ewa Sicinska ◽

Samuel Moss ◽

Stephen P. Remillard ◽

...

Keyword(s):

Targeted Therapy ◽

Tyrosine Kinases ◽

Receptor Tyrosine Kinases ◽

Downstream Signaling ◽

Functional Profiling

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p190RhoGAP is the convergence point of adhesion signals from α5β1 integrin and syndecan-4

The Journal of Cell Biology ◽

10.1083/jcb.200711129 ◽

2008 ◽

Vol 181 (6) ◽

pp. 1013-1026 ◽

Cited By ~ 75

Author(s):

Mark D. Bass ◽

Mark R. Morgan ◽

Kirsty A. Roach ◽

Jeffrey Settleman ◽

Andrew B. Goryachev ◽

...

Keyword(s):

Adhesion Formation ◽

Focal Adhesions ◽

Dependent Manner ◽

Rhoa Activity ◽

Focal Adhesion Formation ◽

Convergence Point ◽

Individual Contributions ◽

Guanosine Triphosphatase ◽

Extracellular Matrix Receptors ◽

Α5β1 Integrin

The fibronectin receptors α5β1 integrin and syndecan-4 cocluster in focal adhesions and coordinate cell migration by making individual contributions to the suppression of RhoA activity during matrix engagement. p190Rho–guanosine triphosphatase–activating protein (GAP) is known to inhibit RhoA during the early stages of cell spreading in an Src-dependent manner. This paper dissects the mechanisms of p190RhoGAP regulation and distinguishes the contributions of α5β1 integrin and syndecan-4. Matrix-induced tyrosine phosphorylation of p190RhoGAP is stimulated solely by engagement of α5β1 integrin and is independent of syndecan-4. Parallel engagement of syndecan-4 causes redistribution of the tyrosine-phosphorylated pool of p190RhoGAP between membrane and cytosolic fractions by a mechanism that requires direct activation of protein kinase C α by syndecan-4. Activation of both pathways is necessary for the efficient regulation of RhoA and, as a consequence, focal adhesion formation. Accordingly, we identify p190RhoGAP as the convergence point for adhesive signals mediated by α5β1 integrin and syndecan-4. This molecular mechanism explains the cooperation between extracellular matrix receptors during cell adhesion.

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Roles of Erbb family receptor tyrosine kinases and downstream signaling pathways in the control of cell growth and survival

Frontiers in Bioscience ◽

10.2741/a782 ◽

2002 ◽

Vol 7 (4) ◽

pp. d376-389 ◽

Cited By ~ 3

Author(s):

Paul Dent

Keyword(s):

Cell Growth ◽

Signaling Pathways ◽

Tyrosine Kinases ◽

Receptor Tyrosine Kinases ◽

Growth And Survival ◽

Erbb Family ◽

Downstream Signaling ◽

Cell Growth And Survival

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Involvement of N-glycan in Multiple Receptor Tyrosine Kinases Targeted by Ling-Zhi-8 for Suppressing HCC413 Tumor Progression

Cancers ◽

10.3390/cancers11010009 ◽

2018 ◽

Vol 11 (1) ◽

pp. 9 ◽

Cited By ~ 2

Author(s):

Ren-In You ◽

Wen-Sheng Wu ◽

Chuan-Chu Cheng ◽

Jia-Ru Wu ◽

Siou-Mei Pan ◽

...

Keyword(s):

Cell Migration ◽

Tyrosine Kinases ◽

Poor Prognosis ◽

Tumor Metastasis ◽

Receptor Tyrosine Kinases ◽

Target Therapy ◽

Downstream Signaling ◽

The Poor ◽

And Function ◽

Multiple Receptor

The poor prognosis of hepatocellular carcinoma (HCC) is resulted from tumor metastasis. Signaling pathways triggered by deregulated receptor tyrosine kinases (RTKs) were the promising therapeutic targets for prevention of HCC progression. However, RTK-based target therapy using conventional kinase-based inhibitors was often hampered by resistances due to compensatory RTKs signaling. Herein, we report that Ling-Zhi-8 (LZ-8), a medicinal peptide from Ganoderma lucidium, was effective in suppressing cell migration of HCC413, by decreasing the amount and activity of various RTKs. These led to the suppression of downstream signaling including phosphorylated JNK, ERK involved in HCC progression. The capability of LZ-8 in targeting multiple RTKs was ascribed to its simultaneous binding to these RTKs. LZ-8 may bind on the N-linked glycan motif of RTKs that is required for their maturation and function. Notably, pretreatment of the N-glycan trimming enzyme PNGase or inhibitors of the mannosidase (N-glycosylation processing enzyme), kifunensine (KIF) and swainsonine (SWN), prevented LZ-8 binding on the aforementioned RTKs and rescued the downstream signaling and cell migration suppressed by LZ-8. Moreover, pretreatment of KIF prevented LZ-8 triggered suppression of tumor growth of HCC413. Our study suggested that a specific type of N-glycan is the potential target for LZ-8 to bind on multiple RTKs for suppressing HCC progression.

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