Cancer-derived mutations in the fibronectin III repeats of PTPRT/PTPrho inhibit cell-cell aggregation.
Abstract The receptor protein tyrosine phosphatase T PTPrho is the most frequently mutated tyrosine phosphatase in human cancer. PTPrho mediates homophilic cell-cell aggregation. In its extracellular region, PTPrho has cell adhesion molecule-like motifs, including a MAM domain, an immunoglobulin domain, and four fibronectin type III (FNIII) repeats. Tumor-derived mutations have been identified in all of these extracellular domains. Previously, the authors determined that tumor-derived mutations in the MAM and immunoglobulin domains of PTPrho reduce homophilic cell-cell aggregation. In this paper, the authors describe experiments in which the contribution of the FNIII repeats to PTPrho-mediated cell-cell adhesion was evaluated. The results demonstrate that deletion of the FNIII repeats of PTPrho result in defective cell-cell aggregation. Furthermore, all of the tumor-derived mutations in the FNIII repeats of PTPrho also disrupt cell-cell aggregation. These results further support the hypothesis that mutational inactivation of PTPrho may lead to cancer progression by disrupting cell-cell adhesion.
Department of Genetics, Case Western Reserve University, Cleveland, Ohio 44106, USA
Peng
P
Zhang
Scott
S
Becka
Sonya E L
SE
Craig
David T
DT
Lodowski
Susann M
SM
Brady-Kalnay
Zhenghe
Z
Wang
D000818:Animals; D002449:Cell Aggregation / Q000235:genetics*; D002460:Cell Line; D005353:Fibronectins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
D005353:Fibronectins; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2