Rho family-associated kinases PAK1 and rock.
Rho family GTPases (Rho, Rac and CDC42) share around 30% sequence identity with RAS family GTPases, and are essential for RAS-induced malignant transformation, i.e., aberrant serum/anchorage-independent growth and actin cytoskeleton-linked morphological changes. Oncogenic RAS mutants such as v-Ha-RAS trigger cell cycle entry (G0-G1 transition) mainly by up-regulating cyclin D1, an activator of cyclin-dependent kinases (CDK), and down-regulating p27, a CDK inhibitor. Although both Rac and CDC42 are clearly activated by RAS, there is so far no evidence that RAS activates Rho. In this chapter, we will discuss the role of these Rho family GTPases and their effectors, in particular the Ser/Thr kinases PAK1 and Rock, in RAS-induced serum/anchorage-independent cell cycling, and discuss several potential therapeutics, peptides or chemical compounds, that could block this oncogenic cell cycle signalling pathway.
Ludwig Institute for Cancer Research, PO Box 2008, Royal Melbourne Hospital, Parkville/Melbourne, Australia 3050.
Hiroshi
H
Maruta
Thao V
TV
Nheu
Hong
H
He
Yumiko
Y
Hirokawa
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054462:p21-Activated Kinases; D054460:rho-Associated Kinases
D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; C515903:PAK1 protein, human; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D054460:rho-Associated Kinases