Enhancement of Notch receptor maturation and signaling sensitivity by Cripto-1
نویسندگان
چکیده
Nodal and Notch signaling pathways play essential roles in vertebrate development. Through a yeast two-hybrid screening, we identified Notch3 as a candidate binding partner of the Nodal coreceptor Cripto-1. Coimmunoprecipitation analysis confirmed the binding of Cripto-1 with all four mammalian Notch receptors. Deletion analyses revealed that the binding of Cripto-1 and Notch1 is mediated by the Cripto-1/FRL-1/Cryptic domain of Cripto-1 and the C-terminal region of epidermal growth factor-like repeats of Notch1. Binding of Cripto-1 to Notch1 occurred mainly in the endoplasmic reticulum-Golgi network. Cripto-1 expression resulted in the recruitment of Notch1 protein into lipid raft microdomains and enhancement of the furin-like protein convertase-mediated proteolytic maturation of Notch1 (S1 cleavage). Enhanced S1 cleavage resulted in the sensitization to ligand-induced activation of Notch signaling. In addition, knockdown of Cripto-1 expression in human and mouse embryonal carcinoma cells desensitized the ligand-induced Notch signaling activation. These results suggest a novel role of Cripto-1 in facilitating the posttranslational maturation of Notch receptors.
منابع مشابه
Protein O-fucosyltransferase 1 is an essential component of Notch signaling pathways.
Notch receptor signaling regulates cell growth and differentiation, and core components of Notch signaling pathways are conserved from Drosophila to humans. Fringe glycosyltransferases are crucial modulators of Notch signaling that act on epidermal growth factor (EGF)-like repeats in the Notch receptor extracellular domain. The substrate of Fringe is EGF-O-fucose and the transfer of fucose to N...
متن کاملBiological and Clinicopathological Significance of Cripto-1 Expression in the Progression of Human ESCC
Background: Human Cripto-1, a member of the EGF-CFC family, is involved in embryonic development, embryonic stem cell maintenance, and tumor progression. It also participates in multiple cell signaling pathways including Wnt, Notch, and TGF-β. Remarkably, it is expressed in cancer stem cell (CSC) compartments, boosting tumor cell migration, invasion, and angiogenesis. Although Cripto-1 is ...
متن کاملNovel Biochemical And Phenotypical Findings On The Nodal Signaling Components Lefty And Cripto
NOVEL BIOCHEMICAL AND PHENOTYPICAL FINDINGS ON THE NODALSIGNALING COMPONENTS LEFTY AND CRIPTObyAMAPOLA BALANCIODecember 2014Advisor: Dr. William Branford, Jr.Major: Biological Sciences (Molecular and Developmental Biology)Degree: Master of ScienceNodal, a Transforming Growth Factor-β (TGF-B), is a key regulator of properdevelopment along with its atypical...
متن کاملCripto forms a complex with activin and type II activin receptors and can block activin signaling.
Activin, nodal, Vg1, and growth and differentiation factor 1 are members of the transforming growth factor beta superfamily and signal via the activin type II (ActRII/IIB) and type I (ALK4) serine/threonine kinase receptors. Unlike activins, however, signaling by nodal, Vg1, and growth and differentiation factor 1 requires a coreceptor from the epidermal growth factor-Cripto-FRL1-Cryptic protei...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
دوره 187 شماره
صفحات -
تاریخ انتشار 2009