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J Biol Chem, Vol. 274, Issue 8, 4551-4560, February 19, 1999
§,§,¶, and§
From the Rho family GTPases regulate multiple cellular
processes, including cytoskeletal organization, gene expression, and
transformation. These effects are achieved through the interaction of
GTP-bound proteins with various downstream targets. A series of
RhoA/Rac1 and Rho/Ras chimeras was generated to map the domain(s) of
RhoA involved in its association with two classes of effector kinase, represented by PRK2 and ROCK-I. Although the switch 1 domain was required for effector binding, the N terminus of Rho (residues 1-75)
was interchangeable with that of Rac. This suggested that the region of
Rho that confers effector binding specificity lay further C-terminal.
Subsequent studies indicated that the "insert domain"(residues
123-137), a region unique to Rho family GTPases, is not the
specificity determinant. However, a determinant for effector binding
was identified between Rho residues 75-92. Rac to Rho point mutations
(V85D or A88D) within loop 6 of Rac promoted its association with PRK2
and ROCK, whereas the reciprocal Rho(D87V/D90A) double mutant
significantly reduced effector binding capacity. In vivo
studies showed that microinjection of Rac(Q6IL/V85D/A88D) but not
Rac(Q6IL) induced stress fiber formation in LLC-PK epithelial cells,
suggesting that loop 6 residues conferred the ability of Rac to
activate ROCK. On the other hand, the reciprocal Rho (Q6IL/D87V/D90A) mutant was defective in its ability to transform NIH 3T3 cells. These
data suggest that although Rho effectors can utilize a Rho or Rac
switch 1 domain to sense the GTP-bound state of Rho, unique residues
within loop 6 are essential for determining both effector binding
specificity and cellular function.
Department of Biochemistry and Molecular
Biology and the § Walther Oncology Center, ¶ Division
of Nephrology, Indiana University School of Medicine,
Indianapolis, Indiana 46202
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