Identification of an Autoinhibitory Domain of p21-activated Protein Kinase 5

Ching, Yick–Pang; Leong, Veronica Yee-Law; Wong, Chi Ming; Kung, Hsiang Fu

doi:10.1074/jbc.c300234200

Cited by 75 publications

(44 citation statements)

References 12 publications

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“…15,23,24 Nevertheless, group B Paks are activated by completely different mechanisms than the group A Paks, and they function as monomers rather than as dimers. 15 In fact, the group B Paks are usually found to be constitutively autophosphorylated at the A-loop, even in quiescent cells.…”

Section: Pak Structure and Activationmentioning

confidence: 99%

P21 activated kinases

Rane¹,

Minden²

2014

Small GTPases

190

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Section: Pak Structure and Activationmentioning

confidence: 99%

P21 activated kinases

Rane¹,

Minden²

2014

Small GTPases

190

View full text Add to dashboard Cite

“…We generated constructs lacking the polybasic region and/or the CRIB motif (ΔPB, ΔCRIB, ΔPB&CRIB) as well as a CRIB motif mutant, H20,23L (HH/LL), previously shown to prevent type II PAK binding to Cdc42 (Fig. 3A,B) (Ching et al, 2003;Menzel et al, 2007). We found that the PAK6 CRIB motif is required for localization to cell-cell adhesions, given that constructs lacking the CRIB motif (ΔCRIB and ΔPB&CRIB) or with a mutated CRIB motif (HH/LL) are diffusely cytoplasmic and no longer target to cell-cell adhesions identified by F-actin or β-catenin staining (Fig.…”

Section: Pak6 Targets To Cell-cell Adhesionsmentioning

confidence: 99%

PAK6 targets to cell-cell adhesions via its N-terminus in a Cdc42-dependent manner to drive epithelial colony escape

Morse

Sun

Olberding

et al. 2015

Journal of Cell Science

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The six serine/threonine kinases in the p21-activated kinase (PAK) family are important regulators of cell adhesion, motility and survival. PAK6, which is overexpressed in prostate cancer, was recently reported to localize to cell-cell adhesions and to drive epithelial cell colony escape. Here we report that PAK6 targeting to cell-cell adhesions occurs through its N-terminus, requiring both its Cdc42/ Rac interactive binding (CRIB) domain and an adjacent polybasic region for maximal targeting efficiency. We find PAK6 localization to cell-cell adhesions is Cdc42-dependent, as Cdc42 knockdown inhibits PAK6 targeting to cell-cell adhesions. We further find the ability of PAK6 to drive epithelial cell colony escape requires kinase activity and is disrupted by mutations that perturb PAK6 cell-cell adhesion targeting. Finally, we demonstrate that all type II PAKs (PAK4, PAK5 and PAK6) target to cell-cell adhesions, albeit to differing extents, but PAK1 (a type I PAK) does not. Notably, the ability of a PAK isoform to drive epithelial colony escape correlates with its targeting to cell-cell adhesions. We conclude that PAKs have a broader role in the regulation of cell-cell adhesions than previously appreciated.

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“…PAK5, the most recently characterized member, contains 719 residues, binds Cdc42, and occurs mainly in the brain Pandey et al, 2002). It contains a CRIB motif around residues 9 -30 and an inhibitory KI motif around residues 120 -133 (Ching et al, 2003). The kinase domain extends from about ϳ453-700.…”

mentioning

confidence: 99%

PAK5 Kinase Is an Inhibitor of MARK/Par-1, Which Leads to Stable Microtubules and Dynamic Actin

Matenia

Griesshaber

et al. 2005

MBoC

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MARK/Par-1 is a kinase involved in development of embryonic polarity. In neurons, MARK phosphorylates tau protein and causes its detachment from microtubules, the tracks of axonal transport. Because the target sites of MARK on tau occur at an early stage of Alzheimer neurodegeneration, we searched for interaction partners of MARK. Here we report that MARK2 is negatively regulated by PAK5, a neuronal member of the p21-activated kinase family. PAK5 suppresses the activity of MARK2 toward its target, tau protein. The inhibition requires the binding between the PAK5 and MARK2 catalytic domains, but does not require phosphorylation. In transfected Chinese hamster ovary (CHO) cells both kinases show a vesicular distribution with partial colocalization on endosomes containing AP-1/2. Although MARK2 transfected alone destabilizes microtubules and stabilizes actin stress fibers, PAK5 keeps microtubules stable through the downregulation of MARK2 but destabilizes the F-actin network so that stress fibers and focal adhesions disappear and cells develop filopodia. The results point to an inverse relationship between actin-and microtubule-related signaling by the PAK5 and MARK2 pathways that affect both cytoskeletal networks. INTRODUCTIONThe observations reported here originated from a study of the neuronal microtubule-associated protein tau and its abnormal changes in Alzheimer's disease. The function of tau in healthy neurons is to stabilize microtubules and to ensure axonal transport along microtubules. In degenerating neurons, tau is hyperphosphorylated, detaches from microtubules, and aggregates into pathological "paired helical filaments." The detachment from microtubules is achieved most efficiently by phosphorylating the KXGS-motifs in the microtubule-binding domain of tau, and elevated phosphorylation at these sites occurs early in Alzheimer's disease (Augustinack et al., 2002). A search for the responsible kinase lead to the identification of the MARK family of protein kinases (Drewes et al., 1997). They are related to the Par-1 kinases in Caenorhabditis elegans and Drosophila melanogaster, which are involved in the determination of embryonic polarity (reviews, Pellettieri and Seydoux, 2002;Fortini, 2004), and indeed the activity of MARK is important for neuronal polarity as well (Biernat et al., 2002). MARK kinases consist of an N-terminal catalytic domain, followed by UBA, spacer, and tail domains. One requirement for activity is the phosphorylation of a threonine in the activation loop (T208 in MARK2), which keeps the active site accessible to the substrate. In the case of MARKs from mammalian brain this is achieved by the kinase MARKK (Timm et al., 2003). Its activation, like that of MARK, leads to detachment of tau and neuronal degeneration, and similar principles appear to hold for other organisms (Nishimura et al., 2004). On the other hand, as with other multidomain kinases, regulation is likely to take place on several levels (Huse and Kuriyan, 2002). Examples are the binding of a pseudosubstrate peptide int...

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Identification of an Autoinhibitory Domain of p21-activated Protein Kinase 5

Cited by 75 publications

References 12 publications

P21 activated kinases

P21 activated kinases

PAK6 targets to cell-cell adhesions via its N-terminus in a Cdc42-dependent manner to drive epithelial colony escape

PAK5 Kinase Is an Inhibitor of MARK/Par-1, Which Leads to Stable Microtubules and Dynamic Actin

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