Integrin (alpha6beta4) signals through Src to increase expression of S100A4, a metastasis-promoting factor: implications for cancer cell invasion.
Integrin alpha6beta4 is linked to cancer cell motility and invasion in aggressive and metastatic cancer cells. In this study, we showed that expression of the beta4 integrin in MDA-MB-435 cancer cells (MDA-MB-435/beta4) leads to a dramatic increase in expression of a metastasis-promoting factor, S100A4, as determined by affymetrix gene chip microarray, quantitative real-time PCR, and Western blot analysis. Alternatively, knocking down beta4 integrin expression in MDA-MB-231 breast carcinoma cells by shRNA reduced the level of S100A4 expression. The mechanism by which alpha6beta4 enhances S100A4 expression involves Src, Akt, and NFAT. We have further shown that Y1494, a tyrosine residue of the ITIM motif in the cytoplasmic domain of the beta4 integrin subunit, is essential for alpha6beta4-dependent S100A4 expression. Reduction of S100A4 expression by shRNA blocked migration, invasion, and anchorage-independent growth of MDA-MB-435/beta4, SUM-159, and MDA-MB-231 cells. These studies define a novel mechanism by which integrin alpha6beta4 promotes cancer cell motility and invasion, and provides insight into how S100A4 expression is regulated in cancer cells.
Kim
Tae Hyong
TH
Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA.
Kim
Hong Im
HI
Soung
Young Hwa
YH
Shaw
Leslie A
LA
Chung
Jun
J
D020816:Amino Acid Motifs / Q000502:physiology; D000081247:CSK Tyrosine-Protein Kinase; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D015536:Down-Regulation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D039161:Integrin alpha6beta4 / Q000737:chemistry / Q000235:genetics*; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000235:genetics* / Q000503:physiopathology; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics; D019061:src-Family Kinases
D039161:Integrin alpha6beta4; D050778:NFATC Transcription Factors; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C077591:S100A4 protein, human; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D051057:Proto-Oncogene Proteins c-akt