Structure of PAK1 in an Autoinhibited Conformation Reveals a Multistage Activation Switch

Lei, Ming; Lu, Wange; Meng, Weiwei; Parrini, Maria Carla; Eck, Michael J.; Mayer, Bruce J.; Harrison, Stephen C.

doi:10.1016/s0092-8674(00)00043-x

Cited by 489 publications

(566 citation statements)

References 54 publications

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“…We also analyzed the activity of PAK-1 using a phospho-T423 antibody to PAK-1 (ref. 37) in hippocampal lysates prepared from naive mice and from mice 0.5 h after E1 or E3 by immunoblotting. We detected a significant increase in membrane-associated PAK-1 Thr423 levels after E3, when compared with E1 (P < 0.05, Fig.…”

Section: A Rac-1-cdk5-pak-1 Pathway Regulates Extinctionmentioning

confidence: 99%

A hippocampal Cdk5 pathway regulates extinction of contextual fear

et al. 2007

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Treatment of emotional disorders involves the promotion of extinction processes, which are defined as the learned reduction of fear. The molecular mechanisms underlying extinction have only begun to be elucidated. By employing genetic and pharmacological approaches in mice, we show here that extinction requires downregulation of Rac-1 and cyclin-dependent kinase 5 (Cdk5), and upregulation of p21 activated kinase-1 (PAK-1) activity. This is physiologically achieved by a Rac-1-dependent relocation of the Cdk5 activator p35 from the membrane to the cytosol and dissociation of p35 from PAK-1. Moreover, our data suggest that Cdk5/p35 activity prevents extinction in part by inhibition of PAK-1 activity in a Rac-1-dependent manner. We propose that extinction of contextual fear is regulated by counteracting components of a molecular pathway involving Rac-1, Cdk5 and PAK-1. Our data suggest that this pathway could provide a suitable target for therapeutic treatment of emotional disorders.The pathogenesis of emotional disorders, post-traumatic stress disorders in particular, often involves associative learning that links anxiogenic stimuli to certain life experiences 1-4 . These disorders severely affect the lives of patients and are an increasing burden on our societies 1 . Treatment of such disorders generally involves the promotion of extinction processes, which are defined as the reduction of an aversively-motivated behavior 2 . Therefore, understanding the molecular mechanisms underlying extinction may help to develop therapeutic strategies for emotional disorders.A well-established procedure for investigating extinction in rodents is Pavlovian fear conditioning. In this procedure, a single exposure of rodents to a novel context followed by an

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Section: A Rac-1-cdk5-pak-1 Pathway Regulates Extinctionmentioning

confidence: 99%

A hippocampal Cdk5 pathway regulates extinction of contextual fear

et al. 2007

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“…They have an N-terminal regulatory domain that binds Rac or Cdc42 (PBD ϭ p21-binding domain containing the CRIB motif) and is responsible for the inhibition of kinase activity, a C-terminal catalytic domain, and an intervening domain with proline-rich motifs that can dock onto SH3-domains of other molecules such as PIX, Nck, and others. The x-ray structure of PAK1 catalytic and regulatory domains shows that, in its inactive state, this kinase is a dimer coupled by the two regulatory domains, where the kinase-inhibitory motif (KI) reaches into the catalytic cleft and blocks the activation loop of the kinase (Lei et al, 2000(Lei et al, , 2005Parrini et al, 2002). Binding of the G-protein at the CRIB motif of the regulatory domain causes the dissociation of the dimer and opening of …”

Section: Introductionmentioning

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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“…[1][2][3] PAKs are characterized by a highly conserved amino-terminal Cdc42/ Rac interactive binding (CRIB) domain and a carboxyl terminal kinase domain. [4][5][6] Six human PAKs were identified and divided into two groups based on their amino acid sequences and their functions. Group A PAKs (PAK1, 2 and 3) share 80 to 90% sequence identity within their catalytic domains, whereas the recently identified group B PAKs (PAK4, 5 and 6), show only approximately 50% identity to the kinase domains of the group A PAKs.…”

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confidence: 99%

P21‐activated kinase 5 is overexpressed during colorectal cancer progression and regulates colorectal carcinoma cell adhesion and migration

Gong

Wang

et al. 2009

Intl Journal of Cancer

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P21-activated kinase 5 (PAK5) is the recently identified member of the group B p21-activated kinase (PAK) family which are effectors of the small GTPase Cdc42 and Rac1, known to regulate cell motility and activate cell-survival signaling pathways. However, overexpression of PAK5 has not been associated with any cancers so far. Interestingly, we found that PAK5 was overexpressed in a variety of colorectal carcinoma (CRC) cell lines in a Western-blotting examination. Therefore, in this study, we aim to examine the PAK5 expression during CRC progression and to answer if PAK5 is involved in malignant progression of CRC. By immunohistochemistry, our results showed that PAK5 expression was increased with CRC progression through the adenoma to carcinoma sequence, with the most significant increases in invasive and metastatic CRCs (p < 0.0001). Furthermore, increased PAK5 expression was also found with the development of CRC from lower Duke's grades to higher ones (p < 0.01). Moreover, PAK5 was also increased from well to poorly differentiated CRCs (p < 0.01). Using gain and loss of function experiments, we found that PAK5 reduced CRC cell adhesion but promoted their migration on collagen type I. Taken together, our study demonstrated that PAK5 expression increased significantly with malignant progression of CRC and that PAK5 might promote CRC metastasis by regulating CRC cell adhesion and migration. ' UICCKey words: colorectal carcinoma; PAK5; cancer cell adhesion and migration P21-activated kinases (PAKs), a family of serine/threonine kinases, are small GTPase effectors that play important roles in regulating cell shape, movement, proliferation and survival. [1][2][3] PAKs are characterized by a highly conserved amino-terminal Cdc42/ Rac interactive binding (CRIB) domain and a carboxyl terminal kinase domain. [4][5][6] Six human PAKs were identified and divided into two groups based on their amino acid sequences and their functions. Group A PAKs (PAK1, 2 and 3) share 80 to 90% sequence identity within their catalytic domains, whereas the recently identified group B PAKs (PAK4, 5 and 6), show only approximately 50% identity to the kinase domains of the group A PAKs. 6,7 A marked difference between the two PAK groups is the autologous inhibitory sequence in the NH2-terminal regulatory domain found in group A PAKs, with no obvious homologous sequence in group B. 7 Unlike group A PAKs, whose binding of Cdc42 and Rac leads to their activation, Group B PAKs are not strongly activated by GTPase binding. 8 Of the three group B PAKs, PAK4 was the best characterized, involving in cell adhesion, migration, proliferation and activation of cell-survival pathways that lead to protection from apoptosis. 9,10 Our previous study demonstrated that PAK4 regulated integrin avb5-mediated breast carcinoma cell migration. 11 Different PAK family members have different tissue-specific expression patterns. PAK4 was found to be overexpressed in 78% of a variety of human cancer cell lines, 12 whereas PAK5 and PAK6 showed restricted tissue-spe...

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Structure of PAK1 in an Autoinhibited Conformation Reveals a Multistage Activation Switch

Cited by 489 publications

References 54 publications

A hippocampal Cdk5 pathway regulates extinction of contextual fear

A hippocampal Cdk5 pathway regulates extinction of contextual fear

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

P21‐activated kinase 5 is overexpressed during colorectal cancer progression and regulates colorectal carcinoma cell adhesion and migration

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