Human Ste20 homologue hPAK1 links GTPases to the JNK MAP kinase pathway

Brown, Jeffrey L.; Stowers, Lisa; Baer, M; Trejo, JoAnn; Coughlin, Shaun R.; Chant, John

doi:10.1016/s0960-9822(02)00546-8

Cited by 248 publications

(220 citation statements)

References 45 publications

(100 reference statements)

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“…Ste20p is known to act as a MAPKKK activator in the pheromonetransduction pathway coupling both the receptor-activated heterotrimeric G protein and Cdc42p to a MAP kinase cascade (Simon et al, 1995); this points to a similar function for Ste20/PAK kinases in yeasts and other organisms (Ottilie et al, 1995;Vojtek and Cooper, 1995). Indeed, the recently identified human PAK isoform, hPAK1, has been shown to be the GTPase effector which links Cdc42 and Rac1 to the JNK MAP kinase pathway (Brown et al, 1996). In addition, recent studies suggest that Cdc42p might control a wider range of biological processes than previously appreciated, which also should be mediated, at least in part, by protein kinase effectors (Bi and Pringle, 1996) In this report we describe the isolation and characterization of a S. cerevisiae gene named SKM1, which encodes a novel Ste20/PAK-like protein kinase.…”

Section: Introductionmentioning

confidence: 99%

**Characterization of SKM1, a Saccharomyces cerevisiae gene encoding a novel Ste20/PAK‐like protein kinase**

Martı́n

Mendoza

Rodrı́guez-Pachón

et al. 1997

Molecular Microbiology

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SummarySte20/PAK serine/threonine protein kinases have been suggested as playing essential roles in cell signalling and morphogenesis as potential targets of Cdc42 and Rac GTPases. We have isolated and characterized the Saccharomyces cerevisiae SKM1 gene, which codes for a novel member of this family of protein kinases. The amino acid sequence analysis of Skm1p revealed the presence of a PH domain and a putative p21-binding domain near its amino terminus, suggesting its involvement in cellular signalling or cytoskeletal functions. However, deletion of SKM1 produced no detectable phenotype under standard laboratory conditions. Moreover, disruption of each of the two other S. cerevisiae Ste20/PAK-like kinase-encoding genes, STE20 and CLA4, in skm1 backgrounds, showed that Skm1p is not redundant with Ste20p or Cla4p. Interestingly, overexpression of SKM1 led to morphological alterations, indicating a possible role for this protein in morphogenetic control. Furthermore, overproduction of Skm1p lacking its N-terminus caused growth arrest. This effect was also seen when similarly truncated versions of Ste20p or Cla4p were overexpressed. We further observed that overproduction of this C-terminal fragment of Skm1p complements the mating defect of a ste20 mutant strain. These results suggest that the N-terminal domains of S. cerevisiae Ste20/ PAK-like protein kinases share a negative regulatory function and play a role in substrate specificity.

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Section: Introductionmentioning

confidence: 99%

**Characterization of SKM1, a Saccharomyces cerevisiae gene encoding a novel Ste20/PAK‐like protein kinase**

Martı́n

Mendoza

Rodrı́guez-Pachón

et al. 1997

Molecular Microbiology

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“…Together, these results confirm the data derived from the actin staining and show for the first time that Cdc42 is activated by HGF in MDCK cells, with distinct kinetics from Rac activation. Constitutively activated Cdc42 or Rac mutants lead to stimulation of PAK and c-Jun N-terminal kinase (JNK) activity in transiently transfected COS-1, COS-7, and HeLa cells (Bagrodia et al, 1995a;Coso et al, 1995;Minden et al, 1995;Olson et al, 1995;Brown et al, 1996). As further support for Cdc42 and Rac activation by HGF, we investigated if PAK and JNK were activated after stimulation of MDCK cells (Figure 3).…”

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Activation of Cdc42, Rac, PAK, and Rho-Kinase in Response to Hepatocyte Growth Factor Differentially Regulates Epithelial Cell Colony Spreading and Dissociation

Royal

Lamarche-Vane

Lamorte

et al. 2000

MBoC

256

211

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Hepatocyte growth factor (HGF), the ligand for the Met receptor tyrosine kinase, is a potent modulator of epithelial-mesenchymal transition and dispersal of epithelial cells, processes that play crucial roles in tumor development, invasion, and metastasis. Little is known about the Met-dependent proximal signals that regulate these events. We show that HGF stimulation of epithelial cells leads to activation of the Rho GTPases, Cdc42 and Rac, concomitant with the formation of filopodia and lamellipodia. Notably, HGF-dependent activation of Rac but not Cdc42 is dependent on phosphatidylinositol 3-kinase. Moreover, HGF-induced lamellipodia formation and cell spreading require phosphatidylinositol 3-kinase and are inhibited by dominant negative Cdc42 or Rac. HGF induces activation of the Cdc42/Rac-regulated p21-activated kinase (PAK) and c-Jun N-terminal kinase, and translocation of Rac, PAK, and Rho-dependent Rho-kinase to membrane ruffles. Use of dominant negative and activated mutants reveals an essential role for PAK but not Rho-kinase in HGF-induced epithelial cell spreading, whereas Rho-kinase activity is required for the formation of focal adhesions and stress fibers in response to HGF. We conclude that PAK and Rho-kinase play opposing roles in epithelial-mesenchymal transition induced by HGF, and provide new insight regarding the role of Cdc42 in these events. INTRODUCTIONEpithelial-mesenchymal transition and cell migration are required during normal embryonic development and during pathological situations such as the dispersal of tumor cells. Hepatocyte growth factor (HGF) is a multifunctional factor that, in addition to promoting epithelial cell growth and survival, has the ability in vitro to stimulate epithelial cell dissociation, motility, invasion, and the endogenous morphogenic program of epithelial cells in three-dimensional matrix or organ culture Nakamura, 1996, 1997;Montesano et al., 1997). Genetic studies have shown that HGF/Met signaling is essential for normal murine embryological development (Birchmeier and Gherardi, 1998). In addition, HGF/Met signaling was also shown to be involved in angiogenesis (Bussolino et al., 1992;Grant et al., 1993) and has been implicated in the dissociation and migration of muscle precursor cells of the dermomyotome, in the guidance and survival of motor neurons, and in the development and survival of sensory neurons (Birchmeier and Gherardi, 1998). HGF and Met were also shown to play a role in pathological conditions, including tissue regeneration (Matsumoto and Nakamura, 1997), tumorigenesis, and metastasis (Jeffers et al., 1996;Bardelli et al., 1997).The conversion from a sessile to a migratory phenotype requires an extensive remodeling of the actin cytoskeleton (Mitchison and Cramer, 1996). Members of the Rho family of small GTP-binding proteins, including Cdc42, Rac, and Rho, are involved in regulating the organization of the actin cytoskeleton and the assembly of associated integrin com-** Corresponding author. E-mail address: morag@lan1.molonc.mcgill.ca. ...

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“…In mammalian cells there are at least three isoforms of Pak, Pak1 (Paka) (Brown et al, 1996;Knaus et al, 1995;Manser et al, 1994;Martin et al, 1995), Pak2 (Pakg) Teo et al, 1995) and Pak3 (Pakb) (Bagrodia et al, 1995b;Manser et al, 1995). These Pak family protein kinases share similar structural features in that they all have an SH3-binding proline-rich motif and a p21-Binding Domain (PBD) at their amino termini and a catalytic domain at their carboxyl termini.…”

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“…Mammalian Pak kinases have been reported to activate the JNK, p38 and Erk MAP kinase pathways under di erent conditions (Bagrodia et al, 1995a;Brown et al, 1996;Frost et al, 1996Frost et al, , 1997Lu et al, 1997;Polverino et al, 1995;Zhang et al, 1995). Mammalian Cdc42 and Rac1 stimulate the stressactivated signal transduction pathways leading to activation of JNK and p38 (Coso et al, 1995;Minden et al, 1995).…”

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Mechanism of activation of Pak1 kinase by membrane localization

Mayer

1999

Oncogene

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Pak kinases are a family of serine/threonine protein kinases homologous to Ste20p of yeast. Paks can be activated in vivo and in vitro by binding to GTP-bound Cdc42 and Rac1, members of the Rho family of small GTPases implicated in regulating the organization of the actin cytoskeleton. We have previously reported that the SH2/SH3-containing adaptor protein Nck binds Pak kinase through its second SH3 domain. Pak1 can be targeted to the membrane by Nck in response to tyrosine phosphorylation, and membrane association of Pak1 is su cient to increase its speci®c activity. The mechanism whereby Pak is activated by membrane localization, however, is unknown. We show here that expression of three proteins that inhibit Rho-family GTPases by di erent mechanisms (RhoGDI, Bcr and D57Y Cdc42) all block the activation of Pak by a membrane-targeted Nck SH3 domain, demonstrating that the in vivo activation of Pak1 induced by membrane localization is dependent on Rho-family GTPases. This implies that Pak activity can be regulated in cells both by the level of GTP loading of various Rho-family GTPases and the local concentration of Pak relative to these GTPases. Our data also suggest the existence of Rho-family GTPases in addition to Cdc42 and Rac1 that can activate Pak on membranes.

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Human Ste20 homologue hPAK1 links GTPases to the JNK MAP kinase pathway

Cited by 248 publications

References 45 publications

**Characterization of SKM1, a Saccharomyces cerevisiae gene encoding a novel Ste20/PAK‐like protein kinase**

**Characterization of SKM1, a Saccharomyces cerevisiae gene encoding a novel Ste20/PAK‐like protein kinase**

Activation of Cdc42, Rac, PAK, and Rho-Kinase in Response to Hepatocyte Growth Factor Differentially Regulates Epithelial Cell Colony Spreading and Dissociation

Mechanism of activation of Pak1 kinase by membrane localization

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