RECK modulates Notch signaling during cortical neurogenesis by regulating ADAM10 activity

Abstract

We report that during cortical development in the mouse embryo, reversion-inducing cysteine-rich protein with Kazal motifs (RECK) critically regulates Notch signaling by antagonizing the ectodomain shedding of Notch ligands, which is mediated by a disintegrin and metalloproteinase domain 10 (ADAM10). In the embryonic brain, RECK is specifically expressed in Nestin-positive neural precursor cells (NPCs). Reck-deficient NPCs undergo precocious differentiation that is associated with downregulated Nestin expression, impaired Notch signaling and defective self-renewal. These phenotypes were substantially rescued either by enhancing Notch signaling or by suppressing endogenous ADAM10 activity. Consequently, we found that RECK regulates the ectodomain shedding of Notch ligands by directly inhibiting the proteolytic activity of ADAM10. This mechanism appeared to be essential for Notch ligands to properly induce Notch signaling in neighboring cells. These findings indicate that RECK is a physiological inhibitor of ADAM10, an upstream regulator of Notch signaling and a critical modulator of brain development.

SFRPs act as negative modulators of ADAM10 to regulate retinal neurogenesis

“…Notably, similar defects characterize also the cortex of embryos deficient in RECK (reversion-inducing cysteine-rich protein with Kazal motifs), a membrane protein localized to cortical precursor cells, which is thought to inhibit ADAM10 sheddase activity but with Notch ligands as substrates 40 .…”

Hypoxia and RAS-signaling pathways converge on, and cooperatively downregulate, the RECK tumor-suppressor protein through microRNAs

“…Recent papers also point to a link between EMT and cancer stem cells (Mani et al, 2008;Hill et al, 2009;Polyak and Weinberg, 2009). Reck has been implicated in angiogenesis (Oh et al, 2001), directional cell migration (Morioka et al, 2009) and suppression of neuronal differentiation (Muraguchi et al, 2007). Thus, the roles of RECK in hypoxia response, EMT and cancer stem cells are interesting subjects to be explored in future studies.…”

“…Forced expression of RECK in cancer cells results in reduced angiogenesis, invasion and metastasis in animal xenograft models (Takahashi et al, 1998;Oh et al, 2001). Mice lacking a functional Reck gene die around embryonic day 10.5 with reduced tissue integrity and defects in various organs, including blood vessels and the central nervous system (Oh et al, 2001;Muraguchi et al, 2007). Studies on RECK gene regulation may therefore yield important insights into the mechanisms of carcinogenesis as well as mammalian development.…”

Involvement of the SKP2–p27KIP1 pathway in suppression of cancer cell proliferation by RECK

“…RECK was first isolated as a transformation-suppressor gene by cDNA expression cloning (Noda et al, 1989;Takahashi et al, 1998) and found to encode a membraneanchored regulator of several extracellular metalloproteinases, including MMP2, MMP7, MMP9, MT1-MMP, ADAM10 and CD13 (Takahashi et al, 1998;Oh et al, 2001;Miki et al, 2007;Muraguchi et al, 2007;Omura et al, 2009). These proteases have been implicated in tissue remodeling and cleavage of various extracellular molecules under normal and pathological conditions (Sternlicht and Werb, 2001).…”

“…Reck-deficient mice die around embryonic day 10.5 with reduced tissue integrity (accompanied by dramatic reduction in collagen fibrils), arrested vascular development and precocious neuronal differentiation (Oh et al, 2001;Muraguchi et al, 2007;Chandana et al, 2010). Embryo fibroblasts derived from these mice show unstable focal adhesions, increased speed of migration and reduced directional persistence during migration, and the phenotype can be partially suppressed on fibronectin-coated dishes .…”