Phosphorylation of Rab37 by protein kinase C alpha inhibits the exocytosis function and metastasis suppression activity of Rab37.
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ABSTRACT: We previously identified a novel Rab small GTPase protein, Rab37, which plays a critical role in regulating exocytosis of secreted glycoproteins, tissue inhibitor of metalloproteinases 1 (TIMP1) to suppress lung cancer metastasis. Patients with preserved Rab37 protein expression were associated with better prognosis. However, a significant number of the patients with preserved Rab37 expression showed poor survival. In addition, the molecular mechanism for the regulation of Rab37-mediated exocytosis remained to be further identified. Therefore, we investigated the molecular mechanism underlying the dysregulation of Rab37-mediated exocytosis and metastasis suppression. Here, we report a novel mechanism for Rab37 inactivation by phosphorylation. Lung cancer patients with preserved Rab37, low TIMP1, and high PKC? expression profile correlate with worse progression-free survival examined by Kaplan-Meier survival, suggesting that PKC? overexpression leads to dysfunction of Rab37. This PKC?-Rab37-TIMP1 expression profile predicts the poor outcome by multivariate Cox regression analysis. We also show that Rab37 is phosphorylated by protein kinase C? (PKC?) at threonine 172 (T172), leading to attenuation of its GTP-bound state, and impairment of the Rab37-mediated exocytosis of TIMP1, and thus reduces its suppression activity on lung cancer cell motility. We further demonstrate that PKC? reduces vesicle colocalization of Rab37 and TIMP1, and therefore inhibits Rab37-mediated TIMP1 trafficking. Moreover, Phospho-mimetic aspartate substitution mutant T172D of Rab37 significantly promotes tumor metastasis in vivo. Our findings reveal a novel regulation of Rab37 activity by PKC?-mediated phosphorylation which inhibits exocytic transport of TIMP1 and thereby enhances lung tumor metastasis.
SUBMITTER: Tzeng HT
PROVIDER: S-EPMC5752464 | biostudies-literature | 2017 Dec
REPOSITORIES: biostudies-literature
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