TY - JOUR
T1 - RalA mediates v-Src, v-Ras, and v-Raf regulation of CD44 and fibronectin expression in NIH3T3 fibroblasts
AU - Ladeda, Virginia
AU - Frankel, Paul
AU - Feig, Larry A.
AU - Foster, David A.
AU - Bal de Kier Joffe, Elisa
AU - Aguirre-Ghiso, Julio A.
N1 - Funding Information:
We are particularly grateful Dr. Eduardo Farías for helpful discussion and to Alicia Rivelli and Lic. Alejandro Adam for excellent technical assistance. We thank Dr. Jorge Filmus for providing us with the KM210 antibody and Dr. Liliana Ossowski for critical reading of the manuscript. This work was supported by grants from the University of Buenos Aires (TM004), CONICET (PIP 4199/96), the National Agency for Scientific and Technical Promotion (PICT-00712 and 6114), and the Health Ministry (Beca Ramón Carrillo-Arturo Oñativia) from Argentina (to E.B.D.K.J.) and by grants from the National Institutes of Health (CA46677) and the American Cancer Society (BE-243) (to D.A.F.), and a Research Centers in Minority Institutions (RCMI) award from the Division of Research Resources, National Institutes of Health (RR-03037) to Hunter College.
PY - 2001
Y1 - 2001
N2 - Oncogenic transformation of fibroblasts by v-Src and v-Ras is often associated with downregulation of fibronectin (FN) and increased expression of CD44, a receptor for hyaluronan. Both v-Src and v-Ras as well as v-Raf activate phospholipase D through the small GTPase, RalA, an important mediator of transformation and tumorigenesis in vivo. We have therefore investigated whether Rata is involved in the down-regulation of FN and overproduction of CD44 upon oncogenic transformation. We report here that compared to untransfected cells NIH3T3 cells transformed by v-Src, v-Ras, or v-Raf have reduced levels of FN and increased levels of CD44. Moreover, the ability to form extracellular FN fibrils was significantly reduced in the oncogene-transformed cells compared to parental controls. Coexpression of the dominant negative S28N-RalA mutant restored the levels of CD44 and FN and the capacity of v-Src-, v-Ras-, and v-Raf-expressing cells to form extracellular FN fibrils, to those observed in NIH3T3 cells. The data presented here show a novel regulatory role for RalA, which is required for tumor formation in transformed NIH3T3 cells, in mediating the signal transduction pathway activated by v-Src, v-Ras, and v-Raf, that leads to FN downregulation and CD44 overexpression.
AB - Oncogenic transformation of fibroblasts by v-Src and v-Ras is often associated with downregulation of fibronectin (FN) and increased expression of CD44, a receptor for hyaluronan. Both v-Src and v-Ras as well as v-Raf activate phospholipase D through the small GTPase, RalA, an important mediator of transformation and tumorigenesis in vivo. We have therefore investigated whether Rata is involved in the down-regulation of FN and overproduction of CD44 upon oncogenic transformation. We report here that compared to untransfected cells NIH3T3 cells transformed by v-Src, v-Ras, or v-Raf have reduced levels of FN and increased levels of CD44. Moreover, the ability to form extracellular FN fibrils was significantly reduced in the oncogene-transformed cells compared to parental controls. Coexpression of the dominant negative S28N-RalA mutant restored the levels of CD44 and FN and the capacity of v-Src-, v-Ras-, and v-Raf-expressing cells to form extracellular FN fibrils, to those observed in NIH3T3 cells. The data presented here show a novel regulatory role for RalA, which is required for tumor formation in transformed NIH3T3 cells, in mediating the signal transduction pathway activated by v-Src, v-Ras, and v-Raf, that leads to FN downregulation and CD44 overexpression.
KW - CD44
KW - Fibronectin
KW - Oncogenes
KW - RalA
KW - Transformation
KW - Tumorigenesis
UR - http://www.scopus.com/inward/record.url?scp=0034817032&partnerID=8YFLogxK
U2 - 10.1006/bbrc.2001.4845
DO - 10.1006/bbrc.2001.4845
M3 - Article
C2 - 11350063
AN - SCOPUS:0034817032
SN - 0006-291X
VL - 283
SP - 854
EP - 861
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 4
ER -