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Gene Review

CLA4  -  Cla4p

Saccharomyces cerevisiae S288c

Synonyms: N0450, Serine/threonine-protein kinase CLA4, YNL298W
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High impact information on CLA4

  • Despite a cytokinesis defect, cla4 mutants are viable [1].
  • In addition, Cla4 induces phosphorylation of Cdc24, leading to its dissociation from Bem1 at bud tips, thereby ending polarized bud growth in vivo [2].
  • This defect is greatly exacerbated when combined with GTP binding-defective septins; conversely, the septin collar assembly defect of such mutants is suppressed efficiently by CLA4 overexpression [3].
  • Although the precise mechanism of APC inhibition by Cla4t remains to be elucidated, our results suggest that Cla4 and Ste20 may regulate the first wave of cyclinB proteolysis mediated by Cdc20/APC, which has been shown to be crucial for activation of the mitotic exit network (MEN) [4].
  • Cla4-green fluorescent protein localized to sites where the cortical actin cytoskeleton and cell surface growth are polarized, independently of an intact actin cytoskeleton [5].

Biological context of CLA4

  • Thus, septin collar formation may correspond to septin filament assembly, and requires both GTP binding and Cla4-mediated phosphorylation of septins [3].
  • The specific activity of Cla4p was cell cycle regulated, peaking near mitosis [6].
  • In cultures started with unbudded cells, an inhibitor of Chs3p activity, nikkomycin Z, aggravated the abnormalities of cla4 and cdc11 mutants and gave rise to enlarged necks at the mother-bud junction, leading to cell death [7].
  • Loss of Ste20 or Cla4 individually confers distinct phenotypes, implying that they regulate different processes [8].
  • The results indicate that CLA4 is a single-copy gene located on the chromosome V of Y. lipolytica [9].

Anatomical context of CLA4


Associations of CLA4 with chemical compounds

  • Rather, we found that polarized growth induced by mutations in CDC12 and CLA4 or by expression of excess SWE1 was also sensitive to EDTA treatment and was restored by the addition of MnCl(2) but not by the addition of CaCl(2) [12].
  • Remarkably, the substitution of a single amino acid, threonine 818, from Ste20 into an otherwise wild-type Cla4, Cla4D772T, conferred the ability to perform many Ste20-specific functions [13].
  • Here we show that the p21-activated protein kinase-related kinase Cla4 of yeast integrates signaling by Cdc42 and phosphatidylinositol 4-phosphate (PI4P) [11].
  • We found that the Cla4 pleckstrin homology (PH) domain binds in vitro to several phosphoinositide species [11].

Physical interactions of CLA4

  • The identification of Pcl1-interacting proteins that genetically interact with Cla4 may indicate a link between G1 progression and mitotic exit [8].
  • A combination of the Cdc42-binding and PH domains of Cla4 was necessary and sufficient for localization to sites of polarized growth [11].

Regulatory relationships of CLA4

  • Cla4p kinase was activated in vivo by the GTP-bound form of Cdc42p [6].
  • Specifically, Cdc42(D38E)p showed reduced interactions with the Cla4p p21-activated protein kinase and the Bem3p GTPase-activating protein and cdc42(D38E) was the only mutant allele able to complement the Deltacdc42 null mutant [14].
  • Furthermore, when overexpressed, CLA4 induces Lte1 phosphorylation and localization to regions of polarized growth [15].
  • Evidence is presented which suggests that the hyperphosphorylated form of Cla4 is responsible for relaying the signal to activate Gin4 [16].

Other interactions of CLA4

  • Absence of a p21-activated protein kinase (Cla4) perturbs septin collar formation [3].
  • Cla4p is homologous to mammalian p21-activated kinases (PAKs) (kinases activated by the rho-class GTPase Rac or Cdc42) [6].
  • This effect was also seen when similarly truncated versions of Ste20p or Cla4p were overexpressed [17].
  • Here, we identify a genetic interaction between PHO85, which encodes a cyclin-dependent kinase, and CLA4 [8].
  • First, CLA4 and SIT4 were synthetically lethal [18].

Analytical, diagnostic and therapeutic context of CLA4

  • PCR analysis with primers specific for serotype A or D alleles of the CNA1, CLA4, and GPA1 genes revealed that both alleles are often present in serotype AD strains [19].


  1. Ste20-like protein kinases are required for normal localization of cell growth and for cytokinesis in budding yeast. Cvrcková, F., De Virgilio, C., Manser, E., Pringle, J.R., Nasmyth, K. Genes Dev. (1995) [Pubmed]
  2. Phosphorylation of the Cdc42 exchange factor Cdc24 by the PAK-like kinase Cla4 may regulate polarized growth in yeast. Gulli, M.P., Jaquenoud, M., Shimada, Y., Niederhäuser, G., Wiget, P., Peter, M. Mol. Cell (2000) [Pubmed]
  3. Septin collar formation in budding yeast requires GTP binding and direct phosphorylation by the PAK, Cla4. Versele, M., Thorner, J. J. Cell Biol. (2004) [Pubmed]
  4. Budding yeast PAK kinases regulate mitotic exit by two different mechanisms. Chiroli, E., Fraschini, R., Beretta, A., Tonelli, M., Lucchini, G., Piatti, S. J. Cell Biol. (2003) [Pubmed]
  5. PAK-family kinases regulate cell and actin polarization throughout the cell cycle of Saccharomyces cerevisiae. Holly, S.P., Blumer, K.J. J. Cell Biol. (1999) [Pubmed]
  6. Cla4p, a Saccharomyces cerevisiae Cdc42p-activated kinase involved in cytokinesis, is activated at mitosis. Benton, B.K., Tinkelenberg, A., Gonzalez, I., Cross, F.R. Mol. Cell. Biol. (1997) [Pubmed]
  7. Septins, under Cla4p regulation, and the chitin ring are required for neck integrity in budding yeast. Schmidt, M., Varma, A., Drgon, T., Bowers, B., Cabib, E. Mol. Biol. Cell (2003) [Pubmed]
  8. The identification of Pcl1-interacting proteins that genetically interact with Cla4 may indicate a link between G1 progression and mitotic exit. Keniry, M.E., Kemp, H.A., Rivers, D.M., Sprague, G.F. Genetics (2004) [Pubmed]
  9. Cla4 protein kinase is essential for filament formation and invasive growth of Yarrowia lipolytica. Szabo, R. Mol. Genet. Genomics (2001) [Pubmed]
  10. Septin ring assembly requires concerted action of polarisome components, a PAK kinase Cla4p, and the actin cytoskeleton in Saccharomyces cerevisiae. Kadota, J., Yamamoto, T., Yoshiuchi, S., Bi, E., Tanaka, K. Mol. Biol. Cell (2004) [Pubmed]
  11. The p21-activated protein kinase-related kinase Cla4 is a coincidence detector of signaling by Cdc42 and phosphatidylinositol 4-phosphate. Wild, A.C., Yu, J.W., Lemmon, M.A., Blumer, K.J. J. Biol. Chem. (2004) [Pubmed]
  12. Filamentous growth of Saccharomyces cerevisiae is regulated by manganese. Asleson, C.M., Asleson, J.C., Malandra, E., Johnston, S., Berman, J. Fungal Genet. Biol. (2000) [Pubmed]
  13. Identification of p21-activated kinase specificity determinants in budding yeast: a single amino acid substitution imparts Ste20 specificity to Cla4. Keniry, M.E., Sprague, G.F. Mol. Cell. Biol. (2003) [Pubmed]
  14. Saccharomyces cerevisiae cdc42p GTPase is involved in preventing the recurrence of bud emergence during the cell cycle. Richman, T.J., Johnson, D.I. Mol. Cell. Biol. (2000) [Pubmed]
  15. Control of Lte1 localization by cell polarity determinants and Cdc14. Seshan, A., Bardin, A.J., Amon, A. Curr. Biol. (2002) [Pubmed]
  16. Control of mitotic events by the Cdc42 GTPase, the Clb2 cyclin and a member of the PAK kinase family. Tjandra, H., Compton, J., Kellogg, D. Curr. Biol. (1998) [Pubmed]
  17. Characterization of SKM1, a Saccharomyces cerevisiae gene encoding a novel Ste20/PAK-like protein kinase. Martín, H., Mendoza, A., Rodríguez-Pachón, J.M., Molina, M., Nombela, C. Mol. Microbiol. (1997) [Pubmed]
  18. The phosphotyrosyl phosphatase activator, Ncs1p (Rrd1p), functions with Cla4p to regulate the G(2)/M transition in Saccharomyces cerevisiae. Mitchell, D.A., Sprague, G.F. Mol. Cell. Biol. (2001) [Pubmed]
  19. Serotype AD strains of Cryptococcus neoformans are diploid or aneuploid and are heterozygous at the mating-type locus. Lengeler, K.B., Cox, G.M., Heitman, J. Infect. Immun. (2001) [Pubmed]
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