Research ArticleCancer

KIF22 coordinates CAR and EGFR dynamics to promote cancer cell proliferation

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Sci. Signal.  30 Jan 2018:
Vol. 11, Issue 515, eaaq1060
DOI: 10.1126/scisignal.aaq1060

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The EGFR-cytoskeleton connection

Growth factor signaling stimulates cell proliferation and migration, which requires changes in cell-cell adhesion and the cytoskeleton. Increased activity of the growth factor receptor EGFR is implicated in various cancers. Pike et al. found that EGFR signaling directs changes in cell-cell junctions and the cytoskeleton in lung cancer cells by inducing the phosphorylation of the cell adhesion receptor CAR (see also the Focus by Chiasson-MacKenzie and McClatchey). Phosphorylated CAR interacted with the microtubule motor protein KIF22 to stabilize the peripheral microtubule network, which facilitated cell division and anchorage-independent growth associated with metastasis. It also altered the trafficking of EGFR such that its signaling was prolonged. Thus, CAR or KIF22 might be alternative targets for therapeutically inhibiting EGFR signaling in some cancers.

Abstract

The coxsackievirus and adenovirus receptor (CAR) is a transmembrane receptor that plays a key role in cell-cell adhesion. CAR is found in normal epithelial cells and is increased in abundance in various human tumors, including lung carcinomas. We investigated the potential mechanisms by which CAR contributes to cancer cell growth and found that depletion of CAR in human lung cancer cells reduced anchorage-independent growth, epidermal growth factor (EGF)–dependent proliferation, and tumor growth in vivo. EGF induced the phosphorylation of CAR and its subsequent relocalization to cell junctions through the activation of the kinase PKCδ. EGF promoted the binding of CAR to the chromokinesin KIF22. KIF22-dependent regulation of microtubule dynamics led to delayed EGFR internalization, enhanced EGFR signaling, and coordination of CAR dynamics at cell-cell junctions. These data suggest a role for KIF22 in the coordination of membrane receptors and provide potential new therapeutic strategies to combat lung tumor growth.

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