RIN1 Is an ABL Tyrosine Kinase Activator and a Regulator of Epithelial-Cell Adhesion and Migration

Hu, Hailiang; Bliss, Joanne M.; Wang, Ying; Colicelli, John

doi:10.1016/j.cub.2005.03.049

Cited by 118 publications

(153 citation statements)

References 49 publications

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“…They showed that Rin1 interacts with GTP-Ras and thereby competes with Raf1 (28). More recent work from the same group indicates that Rin1 interacts with the tyrosine kinase Abl and that via phosphorylation of CRK and CRKL, Rin1 plays a role in actin remodeling and cell migration in epithelial cells and neurons (30). Abl binds Rin1 through the PRD and SH2 domains of Rin1, the same domains that we have shown to interact with STAM2 and EGFR, respectively.…”

Section: Discussionsupporting

confidence: 61%

“…It is composed of several functional domains: SH2 and proline-rich (29) domains in the N-terminal region and Vps9 and Ras association domains in the C-terminal region. Recent studies have shown that through its interaction with Abl tyrosine kinase, Rin1 mediates actin cytoskeleton remodeling associated with migration and adhesion of epithelial cells (30). Our previous work suggested that Rin1 is an exchange factor for small GTPase Rab5, whose overexpression stimulates EGF-mediated endocytosis (31).…”

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confidence: 99%

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Rin1 Interacts with Signal-transducing Adaptor Molecule (STAM) and Mediates Epidermal Growth Factor Receptor Trafficking and Degradation

Chen

et al. 2007

Journal of Biological Chemistry

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Rin1, the prototype of a new family of multidomain Rab5 exchange factors, has been shown to play an important role in the endocytosis of the epidermal growth factor receptor (EGFR). Herein, we examined the role of Rin1 in the down-regulation of EGFR following EGF stimulation. We observed that overexpression of Rin1 accelerates EGFR degradation in EGF-stimulated cells. In concordance, depletion of endogenous Rin1 by RNA interference resulted in a substantial reduction of EGFR degradation. We showed that Rin1 interacts with signal-transducing adaptor molecule 2 (STAM2), a protein that associates with hepatocyte growth factor-regulated substrate and plays a key role in the endosomal sorting machinery. Green fluorescent protein (GFP)-Rin1 co-localizes with hemagglutinin (HA)-STAM2 and with endogenous hepatocyte growth factor-regulated substrate. Furthermore, wild type STAM2, but not a deletion mutant lacking the SH3 domain, co-immunoprecipitates with endogenous Rin1. This interaction is dependent on the proline-rich domain (PRD) of Rin1 as Rin1⌬PRD, a mutant lacking the PRD, does not interact with STAM2. Moreover, EGFR degradation was not accelerated by expression of the Rin1⌬PRD mutant. Together these results suggest that Rin1 regulates EGFR degradation in cooperation with STAM, defining a novel role for Rin1 in regulating endosomal trafficking. The epidermal growth factor receptor (EGFR)2 plays a central role in cell proliferation, differentiation, survival, and migration (1, 2) and has served as a prototype in growth factor receptor trafficking. Following activation, EGFR with intrinsic tyrosine kinase activity is rapidly internalized by clathrincoated pits (3), sorted through early endosomes, and eventually transported to and degraded within multivesicular bodies (MVB) and lysosomes (4, 5). The process is generally known as receptor down-regulation and is considered to be an important cellular strategy for signal attenuation (6, 7). Alterations in receptor trafficking and signal attenuation have been associated with carcinogenesis (5, 8) and certain developmental processes, which has stimulated interest in the molecular mechanisms that regulate EGFR trafficking and degradation.EGFR targeted for lysosomal degradation is delivered to the MVB by a highly specialized process that begins with receptor ubiquitination and sequestration by elements of the ESCRT (endosomal sorting complex required for transport) complex on the surface of the early endosomes (9, 10). Invagination of the endosomal membrane and delivery of sequestered receptors into the lumen of the MVB is accompanied by receptor deubiquitination and disassembly of the ESCRT complex (11,12). The ESCRT machinery, first identified in yeast as class E Vps (vacuolar protein sorting) mutants (13) and highly conserved among eukaryotic cells (14), is important in targeting EGFR into the lumen of the MVB (15, 16). Substantial progress has been made in identifying the molecular mechanisms involved (12,17). Among the early acting factors are Hrs (hepatocyte growth fa...

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Section: Discussionsupporting

confidence: 61%

mentioning

confidence: 99%

Rin1 Interacts with Signal-transducing Adaptor Molecule (STAM) and Mediates Epidermal Growth Factor Receptor Trafficking and Degradation

Chen

et al. 2007

Journal of Biological Chemistry

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“…Cellular tyrosine phosphatases may be responsible for restricting c-Abl activity, as vanadate exposure resulted in activation of c-Abl in all expressing cells. Reciprocal regulation, whereby a substrate interacts with and activates C3G is a target and effector of c-Abl function A Mitra and V Radha c-Abl to phosphorylate itself is known in the case of Abl targets (Shishido et al, 2001;Hu et al, 2005), but C3G co-expression did not alter c-Abl activity. Phosphorylation of another c-Abl substrate, CrkII, also occurred only in cells showing detachment and condensed chromatin.…”

Section: C3g Is a Target And Effector Of C-abl Functionmentioning

confidence: 99%

F-actin-binding domain of c-Abl regulates localized phosphorylation of C3G: role of C3G in c-Abl-mediated cell death

Mitra

Radha

2010

Oncogene

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“…RIN1 expression was attenuated using short interfering RNA (siRNA) as previously described (28) or short hairpin RNA (shRNA)-mediated RNA interference. The shRNA primers were designed using the BLOCK-iT RNAi Designer algorithm (Invitrogen).…”

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confidence: 99%

“…The shRNA primers were designed using the BLOCK-iT RNAi Designer algorithm (Invitrogen). Primers were attached to a U6 promoter via PCR and subsequently cloned into the M4 lentiviral vector (28) modified to include a blasticidin resistance marker. Virus stocks were generated by standard techniques (28).…”

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confidence: 99%

Integration of Transforming Growth Factor β and RAS Signaling Silences a RAB5 Guanine Nucleotide Exchange Factor and Enhances Growth Factor-Directed Cell Migration

Hu¹,

Milstein²,

Bliss³

et al. 2008

Molecular and Cellular Biology

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Transforming growth factor ␤ (TGF-␤) receptor (T␤R) signaling contributes to normal development as well as tumorigenesis. Here we report that RIN1, a RAB5 guanine nucleotide exchange factor (GEF) and down regulator of receptor tyrosine kinases (RTKs), promotes T␤R signaling through enhanced endocytosis. T␤R activation induces SNAI1 (Snail), a transcription repressor that reduces RIN1 expression, providing a negative feedback mechanism to control T␤R trafficking and downstream signaling. Persistent RAS signaling disrupts this equilibrium by stabilizing SNAI1 protein, resulting in strong silencing of RIN1 and stabilization of RTKs. TGF-␤-induced RIN1 silencing in breast cancer cells prolonged sensitivity to hepatocyte growth factor, a ligand for the MET-type RTK, and enhanced growth factor-directed cell motility. We conclude that in some tumor cells T␤R and RAS signals are integrated through the silencing of RIN1, leading to a reduction in RAB5-mediated endocytosis. These findings shed new light on the basis for distinct interpretations of TGF-␤ signaling by normal versus transformed cells.Cell surface receptor internalization controls the intensity and duration of signaling and, as a consequence, regulates phenotypes such as differentiation, mitosis, and migration (36, 44). The clathrin-dependent endocytosis of receptor tyrosine kinases (RTKs), for example, typically results in down regulation and signal termination. The GTPase RAB5 is a key regulator of early endosome formation and trafficking and hence a control point for receptor function. This small GTPase is itself activated by the guanine nucleotide exchange factor (GEF) RIN1 (50) and other GEFs (9) and inhibited by GTPaseactivating proteins (24,39).Transforming growth factor ␤ (TGF-␤), signaling through a receptor serine/threonine kinase complex (T␤RI/T␤RII or T␤R), has antiproliferative effects on normal epithelial cells (48). Some late-stage tumor cells escape this cytostatic effect and instead respond to TGF-␤ with increased proliferation and enhanced motility that promote metastatic spread (16). Activated T␤R phosphorylates associated SMAD2 and SMAD3 proteins that then accumulate in the nucleus, inducing expression of SNAI1 (Snail) (42), a promoter of cell motility in development and tumor progression (3), and other genes. This signaling pathway is enhanced by the recruitment of effector proteins during clathrin-mediated endocytosis (18,27,38,43). An alternate, clathrin-independent, T␤R internalization pathway targets T␤R to a degradation shunt (46). We describe a dynamic role for RIN1 in T␤R endocytosis and regulation of downstream signal intensity. In addition, we provide evidence that T␤R and RTK signals integrate through down regulation of RIN1, contributing to the profound difference in TGF-␤ response between normal and transformed cells. MATERIALS AND METHODSCell culture, transfections, and transductions. MCF10A, MDA-MB-231, HeLa, and HepG2 cell lines were cultured under standard conditions. Transfections were performed using Polyfect (Qiagen) (M...

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RIN1 Is an ABL Tyrosine Kinase Activator and a Regulator of Epithelial-Cell Adhesion and Migration

Abstract: RIN1 is a directly binding ABL tyrosine kinase activator in cells as well as in a defined-component assay. In response to environmental changes, this novel signal pathway mediates actin remodeling associated with adhesion and migration of epithelial cells.

Cited by 118 publications

References 49 publications

Rin1 Interacts with Signal-transducing Adaptor Molecule (STAM) and Mediates Epidermal Growth Factor Receptor Trafficking and Degradation

Rin1 Interacts with Signal-transducing Adaptor Molecule (STAM) and Mediates Epidermal Growth Factor Receptor Trafficking and Degradation

F-actin-binding domain of c-Abl regulates localized phosphorylation of C3G: role of C3G in c-Abl-mediated cell death

Integration of Transforming Growth Factor β and RAS Signaling Silences a RAB5 Guanine Nucleotide Exchange Factor and Enhances Growth Factor-Directed Cell Migration

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