title: Recruitment of Tiam1 to Semaphorin 4D Activates Rac and Enhances Proliferation, Invasion, and Metastasis in Oral Squamous Cell Carcinoma.
abstract: The semaphorins and the plexins are a family of large, cysteine-rich proteins originally identified as regulators of axon growth and lymphocyte activation that are now known to provide motility and positional information for a number of cell and tissue types. For example, our group and others have shown that some malignancies over express Semaphorin 4D (S4D), which acts through its receptor Plexin-B1 (PB1) on endothelial cells to attract blood vessels from the surrounding stroma for the purpose of supporting tumor growth. While plexins are the known functional receptors for the semaphorins, there is evidence that transmembrane semaphorins may transmit a signal themselves through their short cytoplasmic tail, a phenomenon known as 'reverse signaling.' We used computational methods based upon correlated evolution of sequences of interacting proteins, mutational analysis and in vitro and in vivo measurements of tumor aggressiveness to show that when bound to PB1, transmembrane S4D associates with the Rac GTPase exchange factor T lymphoma invasion and metastasis (Tiam) 1, which activates Rac and promotes proliferation, invasion and metastasis in oral squamous cell carcinoma (OSCC) cells. These results suggest that not only can S4D production by tumor cells affect the microenvironment, but engagement of this semaphorin at the cell surface activates a reverse signaling mechanism that influences tumor aggressiveness in OSCC.
authors.affiliation: Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, 650 W. Baltimore Street, 7-North, Baltimore, MD 21201, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Dept of Biological Sciences, University of Maryland Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, USA.
authors.forename: Maricel G
authors.initials: MG
authors.lastname: Kann
authors.affiliation: Biomedical Informatics Training Program, Stanford University, 1265 Welch Road, Stanford, CA 94305, USA.
authors.forename: Emily K
authors.initials: EK
authors.lastname: Mallory
authors.affiliation: Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, 650 W. Baltimore Street, 7-North, Baltimore, MD 21201, USA.
authors.forename: Ying-Hua
authors.initials: YH
authors.lastname: Yang
authors.affiliation: Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, 650 W. Baltimore Street, 7-North, Baltimore, MD 21201, USA.
authors.forename: Amr
authors.initials: A
authors.lastname: Bugshan
authors.affiliation: Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, 650 W. Baltimore Street, 7-North, Baltimore, MD 21201, USA; Department of Oral Basic & Clinical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
authors.forename: Nada O
authors.initials: NO
authors.lastname: Binmadi
authors.affiliation: Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, 650 W. Baltimore Street, 7-North, Baltimore, MD 21201, USA; Greenebaum Cancer Center, 22 S. Greene Street, Baltimore, MD 21201, USA. Electronic address: jbasile@umaryland.edu.
authors.forename: John R
authors.initials: JR
authors.lastname: Basile
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000737:chemistry / Q000378:metabolism*; D001706:Biopsy; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D015870:Gene Expression; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009062:Mouth Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D009362:Neoplasm Metastasis; D009687:Nuclear Proteins / Q000378:metabolism; D054731:PDZ Domains; D011379:Prognosis; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D040901:Proteomics / Q000379:methods; D039961:Semaphorins / Q000737:chemistry / Q000378:metabolism*; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D014157:Transcription Factors / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; C093224:CD100 antigen; D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; D009687:Nuclear Proteins; C102195:PBRM1 protein, human; D039961:Semaphorins; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C087334:TIAM1 protein, human; D014157:Transcription Factors; D020744:rac GTP-Binding Proteins