Abstract
G protein-coupled receptor kinases (GRKs) are important regulators of G protein-coupled receptor function and mediate receptor desensitization, internalization, and signaling. While GRKs also interact with and/or phosphorylate many other proteins and modify their function, relatively little is known about the cellular localization of endogenous GRKs. Here we report that GRK5 co-localizes with γ-tubulin, centrin, and pericentrin in centrosomes. The centrosomal localization of GRK5 is observed predominantly at interphase and although its localization is not dependent on microtubules, it can mediate microtubule nucleation of centrosomes. Knockdown of GRK5 expression leads to G2/M arrest, characterized by a prolonged G2 phase, which can be rescued by expression of wild type but not catalytically inactive GRK5. This G2/M arrest appears to be due to increased expression of p53, reduced activity of aurora A kinase and a subsequent delay in the activation of polo-like kinase 1. Overall, these studies demonstrate that GRK5 is localized in the centrosome and regulates microtubule nucleation and normal cell cycle progression.
Highlights
G protein-coupled receptor kinases (GRKs) are important regulators of receptor function little is known about their cellular localization
Based on recent evidence that arrestins are localized to centrosomes [25], we evaluated if GRKs are localized in centrosomes
We show that GRK5 is localized to centrosomes during interphase and is mainly associated with the mother centriole
Summary
G protein-coupled receptor kinases (GRKs) are important regulators of receptor function little is known about their cellular localization. This G2/M arrest appears to be due to increased expression of p53, reduced activity of aurora A kinase and a subsequent delay in the activation of polo-like kinase 1 Overall, these studies demonstrate that GRK5 is localized in the centrosome and regulates microtubule nucleation and normal cell cycle progression. A number of studies have implicated kinase independent functions of GRKs in receptor and effector regulation, such as in the case of PTCH1 regulation of cyclin B1 [16], F-actin bundling [17], and G␣q signaling [18] These additional functions of GRKs may be important because the level of these protein kinases can vary in many pathological conditions, such as Alzheimer disease [19], cardiovascular disease [20], and cancer [21]. Decreasing the expression of GRK5 results in a delay in the G2/M transition, stemming from increased expression of p53, decreased aurora kinase A (AUKA) activity, and a delay in polo-like kinase 1 (PLK1) activation
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