Role of RhoA, mDia, and ROCK in cell shape-dependent control of the Skp2-p27kip1 pathway and the G1/S transition.
Cell shape-dependent control of cell-cycle progression underlies the spatial differentials of growth that drive tissue morphogenesis, yet little is known about how cell distortion impacts the biochemical signaling machinery that is responsible for growth control. Here we show that the Rho family GTPase, RhoA, conveys the "cell shape signal" to the cell-cycle machinery in human capillary endothelial cells. Cells accumulating p27(kip1) and arrested in mid G(1) phase when spreading were inhibited by restricted extracellular matrix adhesion, whereas constitutively active RhoA increased expression of the F-box protein Skp2 required for ubiquitination-dependent degradation of p27(kip1) and restored G(1) progression in these cells. Studies with dominant-negative and constitutively active forms of mDia1, a downstream effector of RhoA, and with a pharmacological inhibitor of ROCK, another RhoA target, revealed that RhoA promoted G(1) progression by altering the balance of activities between these two downstream effectors. These data indicate that signaling proteins such as mDia1 and ROCK, which are thought to be involved primarily in cytoskeletal remodeling, also mediate cell growth regulation by coupling cell shape to the cell-cycle machinery at the level of signal transduction.
Mammoto
Akiko
A
Vascular Biology Program, Department of Pathology, Children's Hospital/Harvard Medical School, Boston, Massachusetts 02115, USA.
Huang
Sui
S
Moore
Kimberly
K
Oh
Philmo
P
Ingber
Donald E
DE
D002352:Carrier Proteins / Q000502:physiology*; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002455:Cell Division; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003599:Cytoskeleton / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D005109:Extracellular Matrix / Q000378:metabolism; D016193:G1 Phase; D005799:Genes, Dominant; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016196:S Phase; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D015854:Up-Regulation; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000378:metabolism / Q000502:physiology*
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011994:Recombinant Proteins; D044786:S-Phase Kinase-Associated Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein