SRC induces podoplanin expression to promote cell migration.
Nontransformed cells can force tumor cells to assume a normal morphology and phenotype by the process of contact normalization. Transformed cells must escape this process to become invasive and malignant. However, mechanisms underlying contact normalization have not been elucidated. Here, we have identified genes that are affected by contact normalization of Src-transformed cells. Tumor cells must migrate to become invasive and malignant. Src must phosphorylate the adaptor protein Cas (Crk-associated substrate) to promote tumor cell motility. We report here that Src utilizes Cas to induce podoplanin (Pdpn) expression to promote tumor cell migration. Pdpn is a membrane-bound extracellular glycoprotein that associates with endogenous ligands to promote tumor cell migration leading to cancer invasion and metastasis. In fact, Pdpn expression accounted for a major part of the increased migration seen in Src-transformed cells. Moreover, nontransformed cells suppressed Pdpn expression in adjacent Src-transformed cells. Of >39,000 genes, Pdpn was one of only 23 genes found to be induced by transforming Src activity and suppressed by contact normalization of Src-transformed cells. In addition, we found 16 genes suppressed by Src and induced by contact normalization. These genes encode growth factor receptors, adaptor proteins, and products that have not yet been annotated and may play important roles in tumor cell growth and migration.
Shen
Yongquan
Y
Molecular Biology Department, Stratford, New Jersey 08084.
Chen
Chen-Shan
CS
Molecular Biology Department, Stratford, New Jersey 08084; Graduate School of Biomedical Sciences, University of Medicine and Dentistry of New Jersey, Stratford, New Jersey 08084.
Ichikawa
Hitoshi
H
Cancer Transcriptome Project, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku,Tokyo 104-0045, Japan.
Goldberg
Gary S
GS
Molecular Biology Department, Stratford, New Jersey 08084. Electronic address: gary.goldberg@umdnj.edu.
D000818:Animals; D002461:Cell Line, Transformed; D002465:Cell Movement; D050719:Crk-Associated Substrate Protein / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006720:Homozygote; D008024:Ligands; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D051379:Mice; D008856:Microscopy, Fluorescence / Q000379:methods; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D034741:RNA, Small Interfering / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*; D000098853:Podoplanin
D050719:Crk-Associated Substrate Protein; D008024:Ligands; D008562:Membrane Glycoproteins; D034741:RNA, Small Interfering; D019061:src-Family Kinases; C493842:Bcar1 protein, mouse; C490441:Pdpn protein, mouse; D000098853:Podoplanin