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First published online August 26, 2004
doi: 10.1242/10.1242/jcs.01392

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The genetics of Pak

¹ Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA
² Russian State Medical University, 1 Ostrovitjanova Street, Moscow, 117997, Russia

View larger version (27K): [in a new window]   Fig. 1. Phylogenetic tree of the Pak family. (A) Pak subfamilies. In worms, flies and mammals, Paks fall into two structurally and functionally distinct groups, here termed A (green) and B (blue). Both budding and fission yeast contain an evolutionarily related group of Paks that contain a PH domain at the N-terminus (PH Paks; purple). The three Paks from slime mold form a separate group (yellow), as do the remaining Paks from budding and fission yeast (orange). Ce, Caenorhabditis elegans; Ds, Dictyostelium discoideum; Hs, Homo sapiens; Mm, Mus musculus; Sc, Saccharomyces cerevisiae; Sp, Schizosaccharomyces pombe. (B) Domain structure of Paks. One representative of each Pak subfamily is shown.

View larger version (27K): [in a new window]   Fig. 2. Pak function in budding yeast. (A) Ste20 function. Ste20 is an upstream signaling element in the invasive growth, mating, osmotolerance (not shown) and vegetative growth/cell wall integrity (not shown) MAPK pathways, composed of Ste11, Ste7 and either Kss1 or Fus3. The mating MAPK components are stabilized and insulated by the adaptor protein Ste5. In this pathway, Ste20 is activated by the pheromone receptors Ste2/Ste3 through Ste4, the Gß subunit of the heterotrimeric G protein, composed in addition of Gpa1 (G subunit) and Ste18 (G subunit). The proteins Bmh1/Bmh2 and Hs17 act as positive and negative regulators, respectively, of Ste20 function in the invasive growth pathway. Ste20 associates with its activator Cdc42 as well as the scaffold protein Bem1, which helps anchor Ste20 to a multiprotein signaling complex. Ste20 is regulated in a cell-cycle-dependent fashion by Cdc28-Cln1, and acts upon Myo3 and Bni1 to regulate the actin cytoskeleton during polarized growth. Ras2 is an upstream activator of the invasive growth pathway and acts through Cdc24, a guanine-nucleotide-exchange-factor (GEF) for Cdc42. (B) Cla4 function. Like Ste20, Cla4 is part of a multicomponent complex and can activate MAPK pathways, probably by phosphorylating Ste11. Cla4 has unique functions in mitotic exit and in cytokinesis. As detailed in the text, Cla4 is subject to cell-cycle-dependent activation by Cdc28-Clb2, and is itself a regulator of the cell cycle, phosphorylating Swe1, Lte1, septins and Myo3.

View larger version (29K): [in a new window]   Fig. 3. Fission yeast Pak1. As in budding yeast, fission yeast Pak1 is part of a multicomponent complex, which contains the adaptor Scd2 (Bem1 ortholog), Scd1 (Cdc24 ortholog) and Cdc42. Pak1 is positively regulated by Skb1 and Skb5, and negatively by Skb15. Pak1 activates the mating cascade by physically interacting with Byr2 and affects cell polarity by phosphorylating Tea1 and the Rho-GAP Rga8. Pak1 also genetically interacts with Orb6 as well as with Gef1, a GEF for Cdc42. Byr2 is also regulated by Ras1 and Gpa1 (the G subunit of the heterotrimeric G protein). Ras1 also signals through Scd1. The link between pheromone receptors Mam2/Map3 and Pak1 is not established yet; also it is not known whether the Byr2-Byr1-Spk1 MAPK cascade associates with a scaffold protein. Pak1 and Skb1 directly bind to Cdc2 and inhibit mitosis. Orb6 delays mitosis in a Cdc2-dependent manner (Verde et al., 1998) and is regulated by Skb1 to control cell polarity (Wiley et al., 2003).

View larger version (18K): [in a new window]   Fig. 4. Pak functions in mammalian cells. Paks target the MAPK pathway by phosphorylating Raf1 at Ser338 and Mek1 at Ser298. These phosphorylations are necessary but not sufficient for MAPK activation. Paks also act upon a number of regulators of the cytoskeleton, including filamin, p41Arc, LIMK, merlin, myosin light chain kinase (MLCK) and stathmin. The net effect of these phosphorylations is to increase actin and tubulin polymerization. In addition, Paks phosphorylate steroid receptors such as the estrogen (ER) and progesterone (PR) receptors, which results in their activation, and the transcriptional co-repressor CtBP and the proapoptotic protein BAD, which results in their inactivation.