Regulation of PTEN by Rho small GTPases.
PTEN (phosphatase and tensin homologue) is a phosphatase that dephosphorylates both protein and phosphoinositide substrates. It is mutated in a variety of human tumours and has important roles in a diverse range of biological processes, including cell migration and chemotaxis. PTEN's intracellular localization and presumably activity are regulated by chemoattractants in Dictyostelium and mouse neutrophils. However, the mechanisms for its regulation remain elusive. Here we show that RhoA and Cdc42, members of the Rho family of small GTPases, regulate the intracellular localization of PTEN in leukocytes and human transfected embryonic kidney cells. In addition, active RhoA is able to stimulate the phospholipid phosphatase activity of PTEN in human embryonic kidney cells and leukocytes, and this regulation seems to require RhoA's downstream effector, RhoA-associated kinase (Rock). Furthermore, we have identified key residues on PTEN that are required for its regulation by the small GTPase, and show that small GTPase-mediated regulation of PTEN has a significant role in the regulation of chemotaxis.
Li
Zhong
Z
Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, Connecticut 06030, USA.
Dong
Xuemei
X
Dong
Xiemei
X
Wang
Zhenglong
Z
Liu
Wenzhong
W
Deng
Ning
N
Ding
Yu
Y
Tang
Liuya
L
Hla
Tim
T
Zeng
Rong
R
Li
Lin
L
Wu
Dianqing
D
D000818:Animals; D002633:Chemotaxis / Q000502:physiology; D004023:Dictyostelium / Q000201:enzymology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007962:Leukocytes / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009504:Neutrophils / Q000378:metabolism; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
D047908:Intracellular Signaling Peptides and Proteins; D025521:Tumor Suppressor Proteins; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; C089504:polyphosphoinositide phosphatase; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D020764:cdc42 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein