Pharmaceutical Sciences Faculty Publications

The CNK1 Scaffold Binds Cytohesins and Promotes Insulin Pathway Signaling

Document Type

Article

Publication Date

7-15-2010

Journal Title

Genes & Development

ISSN

1549-5477

Volume

24

Issue

14

First Page

1496

Last Page

1506

DOI

10.1101/gad.1904610

PubMed ID

20634316

PubMed Central® ID

PMC2904940

Abstract

Protein scaffolds play an important role in signal transduction, regulating the localization of signaling components and mediating key protein interactions. Here, we report that the major binding partners of the Connector Enhancer of KSR 1 (CNK1) scaffold are members of the cytohesin family of Arf guanine nucleotide exchange factors, and that the CNK1/cytohesin interaction is critical for activation of the PI3K/AKT cascade downstream from insulin and insulin-like growth factor 1 (IGF-1) receptors. We identified a domain located in the C-terminal region of CNK1 that interacts constitutively with the coiled-coil domain of the cytohesins, and found that CNK1 facilitates the membrane recruitment of cytohesin-2 following insulin stimulation. Moreover, through protein depletion and rescue experiments, we found that the CNK1/cytohesin interaction promotes signaling from plasma membrane-bound Arf GTPases to the phosphatidylinositol 4-phosphate 5-kinases (PIP5Ks) to generate a PIP(2)-rich microenvironment that is critical for the membrane recruitment of insulin receptor substrate 1 (IRS1) and signal transmission to the PI3K/AKT cascade. These findings identify CNK1 as a new positive regulator of insulin signaling.

Keywords

Cell line, Cell membrane, insulin, mass spectrometry, signal transduction

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