Disease relevance of RIN1

• A consistent pattern of RIN1 rearrangements in oral squamous cell carcinoma cell lines supports a breakage-fusion-bridge cycle model for 11q13 amplification [1].
• RIN1 appears to be a valuable probe for investigating the process of gene amplification in general and, specifically, 11q13 amplification in oral cancer [1].
• Fifty-two (51.5%) of 101 colorectal cancer specimens strongly expressed the RIN1 gene compared to the adjacent normal colorectal tissue [2].
• To examine the role of Rin1 in IL3 receptor signaling pathways, Rin1 and deletion mutants were expressed in cells using a retrovirus system [3].

High impact information on RIN1

• Regulation of the oncogenic activity of BCR-ABL by a tightly bound substrate protein RIN1 [4].
• RIN1 is tyrosine phosphorylated and is associated with BCR-ABL in human and murine leukemic cells [4].
• RIN1 exemplifies a new class of effector molecules dependent on the concerted action of the SH3, SH2, and catalytic domains of a cytoplasmic tyrosine kinase [4].
• These biological effects require tyrosine phosphorylation of RIN1 and binding of RIN1 to the Abl-SH2 and SH3 domains [4].
• RIN1 interacts with the "effector domain" of RAS and employs some RAS determinants that are common to, and others that are distinct from, those required for the binding of RAF1, a known RAS effector [5].

Biological context of RIN1

• Knockdown of RIN1 in epithelial-cell lines blocked the induction of CRKL phosphorylation, confirming that RIN1 normally functions as an inhibitor of cell motility [6].
• When expressed in mammalian cells, the RAS binding domain of RIN1 can act as a dominant negative signal transduction blocker [5].
• Protein binding and signaling properties of RIN1 suggest a unique effector function [5].
• A differential pattern of expression and alternate splicing indicate several levels of RIN1 regulation [5].
• These results indicate that RIN1 serves as an inhibitory modulator of neuronal plasticity in aversive memory formation [7].

Anatomical context of RIN1

• RIN1 recognizes endogenous RAS following transient activation by epidermal growth factor, and a portion of RIN1 fractionates to the cell membrane in a manner consistent with a reversible interaction [8].
• RIN1 is an ABL tyrosine kinase activator and a regulator of epithelial-cell adhesion and migration [6].
• RIN1 expression in fibroblasts promotes the formation of membrane spikes; similar effects have been reported for ABL overexpression [6].
• We show that RIN1 is preferentially expressed in postnatal forebrain neurons in which it is localized in dendrites and physically associated with RAS, suggesting a role in RAS-mediated postsynaptic neuronal plasticity [7].
• 2. FISH analysis of 10 11q13-amplified OSCC cell lines revealed high-level RIN1 amplification in two cell lines [1].

Associations of RIN1 with chemical compounds

• CONCLUSIONS: RIN1 is a directly binding ABL tyrosine kinase activator in cells as well as in a defined-component assay [6].
• Ras-activated endocytosis is mediated by the Rab5 guanine nucleotide exchange activity of RIN1 [9].

Regulatory relationships of RIN1

• Activated RAS participates in a stable RAS-RIN1-ABL2 complex and stimulates the tyrosine kinase-activation function of RIN1 [6].
• Rin1 is a multifunctional protein that has been shown to regulate EGF receptor signaling and endocytosis [3].
• RIN1 is also shown to stimulate Rab5 guanine nucleotide exchange, Rab5A-dependent endosome fusion, and EGF receptor-mediated endocytosis [9].
• Together these results suggest that Rin1 regulates EGFR degradation in cooperation with STAM, defining a novel role for Rin1 in regulating endosomal trafficking [10].

Other interactions of RIN1

• We demonstrate that the RAS effector protein RIN1 binds to activated RAS with an affinity (K(d), 22 nM) similar to that observed for RAF1 [8].
• Deletion of the RAS binding domain (RBD) strongly stimulated the ABL2 activation function of RIN1, suggesting that RAS activation results from the relief of RIN1 autoinhibition [6].
• AF-6 contains two putative Ras-associating domains (RA domains) which are seen in several Ras effectors such as RalGDS and RIN1 [11].
• Rin1 is a negative regulator of the IL3 receptor signal transduction pathways [3].
• We conclude that Ras-activated endocytosis is facilitated, in part, by the ability of Ras to directly regulate the Rab5 nucleotide exchange activity of RIN1 [9].

Analytical, diagnostic and therapeutic context of RIN1

• Immunoprecipitation of EGFR is accompanied by co-immunoprecipitation of Rin1 in a time- and ligand-dependent manner [12].

References