p21-activated Kinase 6 (PAK6) Inhibits Prostate Cancer Growth via Phosphorylation of Androgen Receptor and Tumorigenic E3 Ligase Murine Double Minute-2 (Mdm2)

Liu, Tong; Li, Yang; Gu, Hui; Zhu, Gangjie; Li, Jiabin; Cao, Liu; Feng, Lian‐Shun

doi:10.1074/jbc.m112.384289

Cited by 53 publications

(43 citation statements)

References 34 publications

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“…Logos were generated using either positional scanning peptide library data (top) or data from all reported sites of phosphorylation in protein substrates (bottom) as compiled on the PhosphoSitePlus database (98). Sites of phosphorylation for the reported type II PAK substrates androgen receptor, LIMK1, Pacsin-1, Synaptojanin-1, MDM2, and PAR6B, which are not included in PhosphoSitePlus, were taken from the literature (9,16,23,33,38). Logos were generated using the program EnoLOGOS (99) and are scaled such that the height of the letter is proportional to the frequency of the residue at the indicated position.…”

Section: Discussionmentioning

confidence: 99%

Signaling, Regulation, and Specificity of the Type II p21-activated Kinases

Ha¹,

Morse

Turk³

et al. 2015

Journal of Biological Chemistry

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The p21-activated kinases (PAKs) are a family of six serine/ threonine kinases that act as key effectors of RHO family GTPases in mammalian cells. PAKs are subdivided into two groups: type I PAKs (PAK1, PAK2, and PAK3) and type II PAKs (PAK4, PAK5, and PAK6). Although these groups are involved in common signaling pathways, recent work indicates that the two groups have distinct modes of regulation and have both unique and common substrates. Here, we review recent insights into the molecular level details that govern regulation of type II PAK signaling. We also consider mechanisms by which signal transduction is regulated at the level of substrate specificity. Finally, we discuss the implications of these studies for clinical targeting of these kinases.The type II PAKs 2 are members of the Sterile 20 (Ste20) family of STE (homologs of yeast Sterile 7, Sterile 11, and Sterile 20) group serine/threonine kinases. They are important for signaling from small GTPases of the RHO family, particularly the CDC42 (cell division cycle 42) and to a lesser extent RAC (Rasrelated C3 botulinum toxin substrate) isoforms, to the actin cytoskeleton and to growth and survival pathways. Type II PAKs share significant sequence similarity with the well studied type I PAKs (PAK1, PAK2, and PAK3), which are extensively reviewed elsewhere (1-5), but the roles of the type I and type II PAKs in GTPase signaling pathways, and their mechanisms of regulation, differ considerably. In the sections below, we consider the function of the type II PAK serine/threonine kinases in small GTPase pathways, the structural and biochemical basis for their regulation, mechanisms of their targeting to substrates, and some of the current strategies for targeted small molecule inhibition of these enzymes. Type II PAKs in Signal TransductionThe type II PAKs are binding partners of RHO family small GTPases. Their dominant role in signal transduction is as serine/threonine kinases, where transfer of the ␥-phosphate from an ATP molecule to a substrate protein results in consequent regulation of downstream effector pathways. The activation of type II PAK kinase signaling is associated with small GTPase binding, but as discussed below, direct activation does not seem to occur upon small GTPase binding. Rather, GTPases are thought to primarily regulate type II PAKs by controlling their subcellular localization. Type II PAKs also have reported kinase-independent roles as scaffolding proteins, with functions that are still emerging.The type II PAKs are placed at critical nodal points in multiple signaling pathways that are associated with cell growth, cytoskeletal dynamics, cell polarity, survival, and development (6 -8). They are located directly downstream of RHO family GTPase activation. Numerous substrates of type II PAKs have been identified that are thought to act as downstream effectors in distinct cellular processes. For example, direct phosphorylation of LIM kinases (9, 10), p210/␤-catenin (11, 12), slingshot phosphatase (SSH) (13), 14), and PDZ-RHOGEF (15) has...

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Section: Discussionmentioning

confidence: 99%

Signaling, Regulation, and Specificity of the Type II p21-activated Kinases

Ha¹,

Morse

Turk³

et al. 2015

Journal of Biological Chemistry

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“…Most PAKs were considered oncogenic genes, however, emerging evidence indicates that PAKs might have a different, even opposite function in the progress of cancer, such as opposite regulating results of estrogen receptor ␣ (ER␣) by PAK1 and PAK6 (34,35). These differences might be caused by regulating manners, such as a different effect of Cdc42 interaction (36), optimal phosphorylation sites (37), or especially by special substrates, such as the unique substrate AR for PAK6 (13,38). Admittedly, most functions of PAK isoforms were overlapped and studies about unique function were sporadic.…”

Section: Discussionmentioning

confidence: 99%

“…As a well known negative regulator of AR, PAK6 might regulate HCC cell proliferation and apoptosis via orchestrating the AR signaling. Meanwhile, PAK6 could phosphorylate the E3 ligase murine double minute-2 (MDM2) at two novel sites, Thr-158 and Ser-186, suggesting PAK6 might regulate protein ubiquitination mediated by MDM2 (13). Furthermore, PAK6 could interact with CCAAT/enhancer-binding protein ␣ (C/EBP␣), which was a poor prognostic factor in HCC (45)(46)(47).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have proved kinase activity was required for PAK6 inhibiting AR transcriptional activity (13,20).…”

Section: Discussionmentioning

confidence: 99%

“…In prostate cancer, the function of PAK6 was context dependent, with evidence suggesting that PAK6 either promotes or resists disease progress (12,13). Meanwhile, PAK6 was found to be induced by INPP4B to suppress prostate cells invasion (14).…”

Section: Hepatocellular Carcinoma (Hcc)mentioning

confidence: 99%

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Tumor Suppressive Function of p21-activated Kinase 6 in Hepatocellular Carcinoma

Liu

et al. 2015

Journal of Biological Chemistry

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Background: p21-activated kinase 6 (PAK6) plays ambiguous roles in tumorigenesis. Results: PAK6, under epigenetic control of polycomb repressive complex 2 (PRC2), possessed tumor suppressive function in hepatocarcinogenesis, relying partially on its kinase activity and nuclear translocation. Conclusion: Repression of PAK6 might contribute to hepatocarcinogenesis. Significance: This finding provides a novel role and potential underlying mechanism of PAK6 in hepatocarcinogenesis.

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