RIN1 orchestrates the activation of RAB5 GTPases and ABL tyrosine kinases to determine the fate of EGFR

Abstract

SummaryStimulation of epidermal growth factor receptor (EGFR) initiates RAS signaling simultaneously with EGFR internalization. Endocytosed EGFR is then either recycled or degraded. EGFR fate is determined in part by the RAS effector RIN1, a guanine nucleotide exchange factor (GEF) for RAB5 GTPases. EGFR degradation was slowed by RIN1 silencing, enhanced by RIN1 overexpression and accelerated by RIN1 localization to the plasma membrane. RIN1 also directly activates ABL tyrosine kinases, which regulate actin remodeling, a function not previously connected to endocytosis. We report that RIN1-RAB5 signaling favors EGFR downregulation over EGFR recycling, whereas RIN1-ABL signaling stabilizes EGFR and inhibits macropinocytosis. RIN1QM , a mutant that blocks ABL activation, caused EGF-stimulated membrane ruffling, actin remodeling, dextran uptake and EGFR degradation. An ABL kinase inhibitor phenocopied these effects in cells overexpressing RIN1. EGFR activation also promotes RIN1 interaction with BIN1, a membrane bending protein. These findings suggest that RIN1 orchestrates RAB5 activation, ABL kinase activation and BIN1 recruitment to determine EGFR fate.

Endocytosis and Cancer

“…Because Ras potentiates the Rab5 nucleotide exchange activity of Rin1, this interaction augments Rab5A-dependent endosome fusion and EGFRmediated endocytosis. In contrast, Rin1-Abl signaling stabilizes EGFR and inhibits macropinocytosis (Balaji et al 2012).…”

Multifunctional Abl kinases in health and disease

“…EGFR endocytosis is also regulated by RAB5 (also known as RABGEF1), a GTPase that promotes early endosome fusion and subsequent degradation of EGFR in the lysosome (Chen et al, 2009). The activity of RAB5 is regulated by the Ras and Rab interactor 1 (RIN1) that binds and activates the Abl kinases, and is also a guanine nucleotide exchange factor (GEF) for RAB5 (Balaji et al, 2012;Hu et al, 2005). Recent data suggest that binding of the RIN1 SH2 domain to EGFR phosphorylated at tyrosine residues balances RIN1-RAB5-mediated EGFR endocytosis and lysosomal degradation with RIN1-ABLdependent EGFR stabilization by blocking macropinocytosis of the receptor (Balaji et al, 2012) (see poster).…”

“…The activity of RAB5 is regulated by the Ras and Rab interactor 1 (RIN1) that binds and activates the Abl kinases, and is also a guanine nucleotide exchange factor (GEF) for RAB5 (Balaji et al, 2012;Hu et al, 2005). Recent data suggest that binding of the RIN1 SH2 domain to EGFR phosphorylated at tyrosine residues balances RIN1-RAB5-mediated EGFR endocytosis and lysosomal degradation with RIN1-ABLdependent EGFR stabilization by blocking macropinocytosis of the receptor (Balaji et al, 2012) (see poster). Although overexpression of active ABL1 inhibits EGFR internalization, the activity of endogenous ABL1 has been reported to be required for antigen-induced endocytosis of the B-cell receptor (Jacob et al, 2009).…”

Human phosphatase CDC14A regulates actin organization through dephosphorylation of epithelial protein lost in neoplasm

“…EGF treatment of HeLa cells promoted the formation of large plasma membrane ruffles that are characterized by highly dynamic actin rearrangements in their lamellipodia (Fig. 4 A and B; EGF, Dox−) (31,32). Dox-induced expression of hCDC14A inhibited this EGF-induced ruffling of the membranes (Fig.…”