title: Membrane microdomain-associated uroplakin IIIa contributes to Src-dependent mechanisms of anti-apoptotic proliferation in human bladder carcinoma cells.
abstract: Our previous study demonstrated that tyrosine phosphorylation of p145(met)/β-subunit of hepatocyte growth factor receptor by epidermal growth factor receptor and Src contributes to the anti-apoptotic growth of human bladder carcinoma cell 5637 under serum-starved conditions. Here, we show that some other cell lines of human bladder carcinoma, but not other types of human cancer cells, also exhibit Src-dependent, anti-apoptotic proliferation under serum-starved conditions, and that low-density, detergent-insoluble membrane microdomains (MD) serve as a structural platform for signaling events involving p145(met), EGFR, and Src. As an MD-associated molecule that may contribute to bladder carcinoma-specific cellular function, we identified uroplakin IIIa (UPIIIa), an urothelium-specific protein. Results obtained so far revealed: 1) UPIIIa undergoes partial proteolysis in serum-starved cells; 2) a specific antibody to the extracellular domain of UPIIIa inhibits the proteolysis of UPIIIa and the activation of Src, and promotes apoptosis in serum-starved cells; and 3) knockdown of UPIIIa by short interfering RNA also promotes apoptosis in serum-starved cells. GM6001, a potent inhibitor of matrix metalloproteinase (MMP), inhibits the proteolysis of UPIIIa and promotes apoptosis in serum-starved cells. Furthermore, serum starvation promotes expression and secretion of the heparin-binding EGF-like growth factor in a manner that depends on the functions of MMP, Src, and UPIIIa. These results highlight a hitherto unknown signaling network involving a subset of MD-associated molecules in the anti-apoptotic mechanisms of human bladder carcinoma cells.
authors.affiliation: Division of Biotechnology, The Graduate School of Engineering, Kyoto Sangyo University ,  Kyoto 603-8555 ,  Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kihira
authors.forename: Junpei
authors.initials: J
authors.lastname: Yoshida
authors.forename: Yukari
authors.initials: Y
authors.lastname: Kawada
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Hitomi
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Asada
authors.forename: Rie
authors.initials: R
authors.lastname: Hisatomi
authors.forename: Akina
authors.initials: A
authors.lastname: Ohta
authors.forename: Tetsushi
authors.initials: T
authors.lastname: Iwasaki
authors.forename: A K M
authors.initials: AK
authors.lastname: Mahbub Hasan
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Fukami
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Sato