title: GRK3 is essential for metastatic cells and promotes prostate tumor progression.
abstract: The biochemical mechanisms that regulate the process of cancer metastasis are still poorly understood. Because kinases, and the signaling pathways they comprise, play key roles in regulation of many cellular processes, we used an unbiased RNAi in vitro screen and a focused cDNA in vivo screen against human kinases to identify those with previously undocumented roles in metastasis. We discovered that G-protein-coupled receptor kinase 3 (GRK3; or β-adrenergic receptor kinase 2) was not only necessary for survival and proliferation of metastatic cells, but also sufficient to promote primary prostate tumor growth and metastasis upon exogenous expression in poorly metastatic cells in mouse xenograft models. Mechanistically, we found that GRK3 stimulated angiogenesis, at least in part through down-regulation of thrombospondin-1 and plasminogen activator inhibitor type 2. Furthermore, GRK3 was found to be overexpressed in human prostate cancers, especially in metastatic tumors. Taken together, these data suggest that GRK3 plays an important role in prostate cancer progression and metastasis.
authors.affiliation: Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030.
authors.forename: Wenliang
authors.initials: W
authors.lastname: Li
authors.forename: Nanping
authors.initials: N
authors.lastname: Ai
authors.forename: Suming
authors.initials: S
authors.lastname: Wang
authors.forename: Nandita
authors.initials: N
authors.lastname: Bhattacharya
authors.forename: Vladimir
authors.initials: V
authors.lastname: Vrbanac
authors.forename: Michael
authors.initials: M
authors.lastname: Collins
authors.forename: Sabina
authors.initials: S
authors.lastname: Signoretti
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Hu
authors.forename: Frederick M
authors.initials: FM
authors.lastname: Boyce
authors.forename: Karsten
authors.initials: K
authors.lastname: Gravdal
authors.forename: Ole J
authors.initials: OJ
authors.lastname: Halvorsen
authors.forename: Hawa
authors.initials: H
authors.lastname: Nalwoga
authors.forename: Lars A
authors.initials: LA
authors.lastname: Akslen
authors.forename: Ed
authors.initials: E
authors.lastname: Harlow
authors.forename: Randolph S
authors.initials: RS
authors.lastname: Watnick
mesh_terms: D049109:Cell Proliferation; D018450:Disease Progression; D054770:G-Protein-Coupled Receptor Kinase 3 / Q000502:physiology*; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis; D017396:Plasminogen Activator Inhibitor 2 / Q000235:genetics; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D019700:Thrombospondin 1 / Q000235:genetics
chemical_list: D017396:Plasminogen Activator Inhibitor 2; D019700:Thrombospondin 1; D054770:G-Protein-Coupled Receptor Kinase 3; C517848:GRK3 protein, human
keywords: ADRBK2; PAI-2; TSP-1; essential kinases; functional screens