KIF22 coordinates CAR and EGFR dynamics to promote cancer cell proliferation

Abstract

The Coxsackie 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. Here, 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.

EGFR-induced cytoskeletal changes drive complex cell behaviors: The tip of the iceberg

“…In this issue of Science Signaling, Roth et al (11) and Pike et al (12) from the Yarden and Parsons groups, respectively, used different proteomic approaches to uncover new insight into the complex question of how EGF-induced signaling modulates cytoskeletal remodeling during cell migration, adhesion, and division. Roth et al used stable isotope labeling by amino acids in cell culture (SILAC)-based phosphoproteomic analysis to identify previously unknown proteins involved in growth factorinduced migration in mammary epithelial cells (11).…”

Suppression of KIF22 Inhibits Cell Proliferation and Xenograft Tumor Growth in Tongue Squamous Cell Carcinoma

“…KIF22 bound to microtubules which were important in receptor traffic, including EGFR [42,43]. KIF22 regulated microtubule stability and upregulated EGFR signaling which promoted CAR phosphorylation and relocalization at plasma membrane to increase cell division [44].…”

High kinesin family member 18A expression correlates with poor prognosis in primary lung adenocarcinoma

“…Both KIF3 and KIF4 have been identified as tumor suppressor genes in gastric cancer . Pike et al demonstrated that chromokinesin KIF22 was coordinated with coxsackievirus and adenovirus receptor (CAR) and EGFR, two key plasma membrane receptors that facilitate cancer cell division, resulting in the promotion of CAR and EGFR dependent tumorigenesis in lung cancer . Hung et al proposed that KIF14 might regulate the recruitment of the adhesive molecule cadherin 11 to the cell membrane in LUAD cell lines …”

“…18,19 Pike et al demonstrated that chromokinesin KIF22 was coordinated with coxsackievirus and adenovirus receptor (CAR) and EGFR, two key plasma membrane receptors that facilitate cancer cell division, resulting in the promotion of CAR and EGFR dependent tumorigenesis in lung cancer. 20 Hung et al proposed that KIF14 might regulate the recruitment of the adhesive molecule cadherin 11 to the cell membrane in LUAD cell lines. 21 KIF18A, an important member of KIF8 family, plays key roles in the regulation of chromosome congression during prometaphase and in the maintenance of chromosome alignment during metaphase.…”