ERK-MAPK signaling coordinately regulates activity of Rac1 and RhoA for tumor cell motility

Speaker: 張 心 玫

Time: PM 2:00- 3:00; 09/17/2003

Room: 601

Abstract:

Genes underlying loss of cell adhesion and/or increase of motility play critical roles in the transition from a benign to an invasive phenotype in tumor development¹.  Members of Rho family, such as Rac, Cdc42, and RhoA, are known to be key regulators of cellular motility and adhesion.  In terms of cell motility, activation of RhoA, Rac1, or Cdc42 could lead to formation of actin stress fibers, membrane ruffles/lamellipodia, and filopodia, respectively. Both Rac1 and RhoA are downstream effectors of ERK-MAPK pathway.  The ERK-MAPK pathway has been defined as the downstream tranducer of oncogenic Ras signaling, and involves in invasion and motility of the cells.  However, the detailed mechanisms of Rac and Rho related cell motility remains unclear. In this paper, Ras downstream ERK-MAPK pathway was demonstrated to be able to modulate motility and invasion of the tumor cells through regulation of the activity of Rac1 and RhoA.  The authors found that ERK-MAPK pathway down-regulated RhoA and up-regulated the activity of Rac1 through Fra-1 and urokinase-type plasminogen activator receptor (uPAR), respectively.  uPAR is a receptor of urokinase.  Fra-1 is a member of Fos protein family.  The authors also demonstrated that Fra-1 inactivated b1-integrin signaling and reduced the activity of RhoA.  In conclusion, high RhoA activity blocked cell motility induced by Rac1, but low RhoA activity in contrast allowed the second ERK-MAPK pathway utilzing uPAR to activate Rac1, which drived the cell to move.  Cell motility related ERK-MAPK signal transduction might provide a clue for cancer therapy to suppress the motility and invasion of the human cancer cells.

References:

1.      Price, L. S., and Collard, J. G. 2001, Regulation of the cytoskeleton by Rho-family GTPases: implications for tumour cell invasion.  Cancer Biol. 11: 167-173.

2.      Vial, E., Sahai, E., and Marshall, C. J. 2003, ERK-MAPK signaling coordinately regulates activity of Rac1 and RhoA for tumor cell motility.  Cancer Cell. 4: 67-79.