Abstract
G protein-coupled receptor kinases (GRK) regulate diverse cellular functions ranging from metabolism to growth and locomotion. Here, we report an important contributory role for GRK5 in human prostate cancer. Inhibition of GRK5 kinase activity attenuated the migration and invasion of prostate cancer cells and, concordantly, increased cell attachment and focal adhesion formation. Mass spectrometric analysis of the phosphoproteome revealed the cytoskeletal-membrane attachment protein moesin as a putative GRK5 substrate. GRK5 regulated the subcellular distribution of moesin and colocalized with moesin at the cell periphery. We identified amino acid T66 of moesin as a principal GRK5 phosphorylation site and showed that enforcing the expression of a T66-mutated moesin reduced cell spreading. In a xenograft model of human prostate cancer, GRK5 silencing reduced tumor growth, invasion, and metastasis. Taken together, our results established GRK5 as a key contributor to the growth and metastasis of prostate cancer.
Highlights
Prostate cancer is the most common noncutaneous neoplasm diagnosed in the Western male population and is the second leading cause of cancer-related mortality in American men [1]
Overexpression and activating mutations of G protein–coupled receptors (GPCR) are linked to tumor growth, angiogenesis, and metastasis [4, 5], and targeting mutated or deregulated GPCRs are promising in experimental cancer therapy [6]
We examined whether the effects of GRK5 on prostate cancer cell migration and invasion required its kinase activity
Summary
Prostate cancer is the most common noncutaneous neoplasm diagnosed in the Western male population and is the second leading cause of cancer-related mortality in American men [1]. Localized prostate cancer can be successfully managed with radiotherapy or surgery, and prostate cancer– related deaths primarily result from cancer metastasis to distant organs [2]. Cancer metastasis involves the cell local invasion and migration so that detached cells from the primary tumor mass can colonize at distant organs. Molecular mediators involved in the cancer cell migration and invasion may serve as biomarkers and therapeutic targets. G protein–coupled receptors (GPCR) are founding members of the superfamily of seven transmembrane-spanning receptors that regulate physiologic and pathophysiologic processes, including initiation and progression of cancer [3,4,5]. Overexpression and activating mutations of GPCRs are linked to tumor growth, angiogenesis, and metastasis [4, 5], and targeting mutated or deregulated GPCRs are promising in experimental cancer therapy [6].
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