title: EGFR-mediated carcinoma cell metastasis mediated by integrin αvβ5 depends on activation of c-Src and cleavage of MUC1.
abstract: Receptor tyrosine kinases and integrins play an essential role in tumor cell invasion and metastasis. We previously showed that EGF and other growth factors induce human carcinoma cell invasion and metastasis mediated by integrin αvβ5 that is prevented by Src blockade. MUC1, a transmembrane glycoprotein, is expressed in most epithelial tumors as a heterodimer consisting of an extracellular and a transmembrane subunit. The MUC1 cytoplasmic domain of the transmembrane subunit (MUC1.CD) translocates to the nucleus where it promotes the transcription of a metastatic gene signature associated with epithelial to mesenchymal transition. Here, we demonstrate a requirement for MUC1 in carcinoma cell metastasis dependent on EGFR and Src without affecting primary tumor growth. EGF stimulates Src-dependent MUC1 cleavage and nuclear localization leading to the expression of genes linked to metastasis. Moreover, expression of MUC1.CD results in its nuclear localization and is sufficient for transcription of the metastatic gene signature and tumor cell metastasis. These results demonstrate that EGFR and Src activity contribute to carcinoma cell invasion and metastasis mediated by integrin αvβ5 in part by promoting proteolytic cleavage of MUC1 and highlight the ability of MUC1.CD to promote metastasis in a context-dependent manner. Our findings may have implications for the use and future design of targeted therapies in cancers known to express EGFR, Src, or MUC1.
authors.affiliation: Department of Pathology, Moores University of California San Diego Cancer Center, La Jolla, California, USA.
authors.forename: Steven K M
authors.initials: SK
authors.lastname: Lau
authors.forename: David J
authors.initials: DJ
authors.lastname: Shields
authors.forename: Eric A
authors.initials: EA
authors.lastname: Murphy
authors.forename: Jay S
authors.initials: JS
authors.lastname: Desgrosellier
authors.forename: Sudarshan
authors.initials: S
authors.lastname: Anand
authors.forename: Miller
authors.initials: M
authors.lastname: Huang
authors.forename: Shumei
authors.initials: S
authors.lastname: Kato
authors.forename: Ssang-Taek
authors.initials: ST
authors.lastname: Lim
authors.forename: Sara M
authors.initials: SM
authors.lastname: Weis
authors.forename: Dwayne G
authors.initials: DG
authors.lastname: Stupack
authors.forename: David D
authors.initials: DD
authors.lastname: Schlaepfer
authors.forename: David A
authors.initials: DA
authors.lastname: Cheresh
mesh_terms: D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002642:Chick Embryo; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology; D058750:Epithelial-Mesenchymal Transition; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018396:Mucin-1 / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000235:genetics*; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D019030:Receptors, Vitronectin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D019061:src-Family Kinases
chemical_list: C060192:MUC1 protein, human; D018396:Mucin-1; D019030:Receptors, Vitronectin; C064660:integrin alphaVbeta5; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human