Disease relevance of STE20

• Deletion of the kinase domain of STE20 causes sterility in both haploid mating types [1].
• Activation of Ste20 by Nef from human immunodeficiency virus induces cytoskeletal rearrangements and downstream effector functions in Saccharomyces cerevisiae [2].

High impact information on STE20

• Three alleles of BMH1 encode proteins defective for FG(TyA)-lacZ signaling and association with Ste20p, yet these alleles complement other 14-3-3 functions [3].
• Moreover, Bmh1p and Bmh2p associate with Ste20p in vivo [3].
• Considering the high degree of structural and functional conservation of Ste20/PAK family members and G-protein subunits, our results provide a possible model for a role of these kinases in Gbetagamma-mediated signal transduction in organisms ranging from yeast to mammals [4].
• Serine/threonine protein kinases of the Ste20/PAK family have been implicated in the signalling from heterotrimeric G proteins to mitogen-activated protein (MAP) kinase cascades [4].
• We have identified a binding site for the G-protein beta-subunit (Gbeta) in the non-catalytic carboxy-terminal regions of Ste20 and its mammalian homologues, the p21-activated protein kinases (PAKs) [4].

Biological context of STE20

• This work reports the identification, characterization, and nucleotide sequence of STE20, a newly discovered gene involved in the Saccharomyces cerevisiae mating response pathway, to date one of the best understood signal transduction pathways [1].
• However, deletions of STE20 in haploid and diploid greatly diminished these hsl7-associated phenotypes [5].
• Finally, we have found that Bni1p is phosphorylated in vivo, and a substantial portion of this phosphorylation is dependent on STE20 [6].
• Ste20-like protein kinases are required for normal localization of cell growth and for cytokinesis in budding yeast [7].
• In agreement with this, a marked reduction in the electrophoretic mobility of the Ste20 protein is observed at the time in the cell cycle of maximal expression of CLN2 [8].

Anatomical context of STE20

• Lung epithelial cells and extracellular matrix components induce expression of Pneumocystis carinii STE20, a gene complementing the mating and pseudohyphal growth defects of STE20 mutant yeast [9].
• LOK is expressed as a 130-kDa protein, which was detected predominantly in lymphoid organs such as spleen, thymus, and bone marrow, in contrast to other mammalian members of the STE20 family [10].
• In contrast to p42MAPK, activation of JNK/SAPK in Xenopus oocyte extracts was induced by both the yeast Ste20 and Shk1 kinases, as well as by mammalian Pak1 [11].
• Misshapen/NIKs-related kinase (MINK) is a member of the germinal center family of kinases that are homologous to the yeast sterile 20 (Ste20) kinases and regulate a wide variety of cellular processes, including cell morphology, cytoskeletal rearrangement, and survival [12].
• PAKc contains a Rac-GTPase binding (CRIB) and autoinhibitory domain, a PAK-related kinase domain, an N-terminal phosphatidylinositol binding domain, and a C-terminal extension related to the Gbetagamma binding domain of Saccharomyces cerevisiae Ste20, the latter two domains being required for PAKc transient localization to the plasma membrane [13].

Associations of STE20 with chemical compounds

• STE20 encodes a putative serine/threonine-specific protein kinase with a predicted molecular mass of 102 kDa [1].
• High sequence similarity was detected to members of the mitogen-activated serine/threonine protein (MAP) kinase family involved in signal transduction: STE20, STE11, BCK1, Byr2 and p65PAK [14].
• It has an NH2-terminal catalytic domain most similar to that of the Drosophila NinaC protein and the yeast STE20 protein [15].
• Taken together, these findings support a model in which the recruitment of the Ste20 kinase NIK to phosphotyrosine-containing proteins by Nck is an important proximal step in the signaling cascade downstream of EphRs [16].
• Nck-interacting Ste20 kinase couples Eph receptors to c-Jun N-terminal kinase and integrin activation [16].

Physical interactions of STE20

• Our genetic analyses suggest the possibility that Cdc42p and Hsl7p compete for binding to Ste20p for pseudohyphal development when starved for nitrogen [5].
• This function of Ste20 in the HOG pathway requires binding of the small GTPase Cdc42 [17].

Enzymatic interactions of STE20

• RESULTS: Ste20p phosphorylated Ste11p on Ser302 and/or Ser306 and Thr307 in yeast, residues that are conserved in MEKKs of other organisms [18].

Regulatory relationships of STE20

• Thus, Hsl7p may inhibit the activity of Ste20p in the S. cerevisiae filamentous growth-signaling pathway [5].
• We therefore propose that Akr1p negatively affects the activity of a protein that both controls cell shape and contributes to the pheromone response pathway upstream of Ste20p but downstream of G beta gamma [19].
• Together, these results suggest that one function of Ste20p may be to activate the polarisome complex by phosphorylation of Bni1p [6].
• Ste20 activates Ste11 by derepressing an autoinhibitory domain [20].
• In addition, these point mutants were synthetically lethal with disruption of CLA4 and blocked the Ste20p-Cdc42p two-hybrid interaction [21].

Other interactions of STE20

• Cla4 and Ste20 kinases apparently share a function in localizing cell growth with respect to the septin ring [7].
• Hsl7p, a negative regulator of Ste20p protein kinase in the Saccharomyces cerevisiae filamentous growth-signaling pathway [5].
• Thus, binding of Gbetagamma to the RING-H2 domain may induce a conformational change that promotes association of the N- and C-terminal ends of Ste5, stimulating activation of the MAPK cascade by optimizing orientation of the bound kinases and/or by increasing their accessibility to Ste20-dependent phosphorylation (or both) [22].
• Two morphogenic pathways for which Ste20 is essential, pseudohyphal differentiation and haploid-invasive growth, also require CLN1 and CLN2 [8].
• This effect was also seen when similarly truncated versions of Ste20p or Cla4p were overexpressed [23].

Analytical, diagnostic and therapeutic context of STE20

• A STE20/p65pak homolog was isolated from fission yeast by PCR [24].
• Molecular cloning and characterization of a novel putative STE20-like kinase in guinea pigs [25].
• The serine/threonine kinase Mst1, a mammalian homolog of the budding yeast Ste20 kinase, is cleaved by caspase-mediated proteolysis in response to apoptotic stimuli such as ligation of CD95/Fas or treatment with staurosporine [26].

References