课题基金 / 基金详情

Sonic Hedgehog is a Calcium-regulated Zinc peptidase

Sonic Hedgehog is a Calcium-regulated Zinc peptidase
Sonic Hedgehog 是一种钙调节锌肽酶
批准号:
10308712
负责人:
HENK ROELINK
金额:
$32.94万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-02-01 至 2022-11-30

项目摘要

项目成果

HENK ROELINK的其他基金

相似基金

相关文献

中文摘要
翻译
刺猬(Hh)信号在包括哺乳动物在内的大多数动物的发育过程中起着核心作用
英文摘要
Hedgehog (Hh) signaling plays a central role during development in most animals, including mammals, while aberrant activation of the Hh response is associated with common cancers. Hhs are synthesized as pro-proteins that undergo an autoproteolytic event yielding the active N-terminal domain (HhN), and a C-terminal domain (HhC). HhN has 3 domains: its N-terminus binds the Hh receptor Patched (Ptch), the middle domain binds calcium (Ca) and the third domain coordinates zinc (Zn). The Ca- and Zn-binding domains (the bulk of HhN) are up to 65% identical to some bacterial peptidases (BacHhs), including all residues predicted to mediate catalysis and allosteric regulation. Many of these conserved residues are found mutated in holoprosencephaly, a congenital birth defect, emphasizing their importance for normal Hh function. Preliminary studies show that the peptidase activity intrinsic to Shh (a vertebrate Hh) is required for its release into the extracellular matrix (ECM) and the supernatant and thus for non-cell autonomous signaling. The inclusion of Shh in a highly conserved family of peptidases that spans multiple domains of life, combined with observations that the peptidase activity of Shh is required for Shh distribution and signaling form the premise of the hypothesis that ShhN is a Ca- regulated Zn-peptidase that mediates its release to allow non-cell autonomous signaling. Using Shh mutants in addition to BacHh/Shh mosaics, Aim1 will examine Shh residues that are required for catalysis, substrate recognition, and Ca regulation by assessing Shh distribution and signaling. Aim 2 will determine the substrates of Shh-mediated catalysis. Two plausible, non-mutually exclusive, substrates for Shh are Shh itself, including the removal of hydrophobic anchors or the release of the Ptch1-dinding domain, and ECM proteoglycans. In particular, heparan sulphate proteoglycans (HSPGs) that affect Shh signaling and extracellular distribution are assessed as substrates. Further characterization of the Shh-associated peptidase activity and identification of substrates will have major ramification in understanding the role of Shh as a developmental morphogen and will likely provide new targets to suppress non-cell autonomous Shh signaling that is a driving force in several cancers.
期刊论文(8)
专著(0)
科研奖励(0)
会议论文
DOI: 10.1186/s12860-021-00359-5
发表时间: 2021-04-16
期刊: BMC molecular and cell biology
影响因子: 2.8
作者: [Jägers C, Roelink H]
通讯作者: Roelink H
Sonic Hedgehog Is a Member of the Hh/DD-Peptidase Family That Spans the Eukaryotic and Bacterial Domains of Life.
Sonic Hedgehog 是跨越真核和细菌生命领域的 Hh/DD 肽酶家族的成员。
DOI: 10.3390/jdb6020012
发表时间: 2018
期刊: Journal of developmental biology
影响因子: 2.7
作者: [Roelink,Henk]
通讯作者: Roelink,Henk
DOI: 10.1002/stem.3018
发表时间: 2019-07
期刊: Stem cells (Dayton, Ohio)
影响因子: --
作者: [Guo W, Roelink H]
通讯作者: Roelink H
DOI: 10.1371/journal.pbio.3001596
发表时间: 2022-03
期刊: PLoS biology
影响因子: 9.8
作者: []
通讯作者:
6
    The roles of Ptch1 and Disp1 in the formation of the Shh gradient
    The roles of Ptch1 and Disp1 in the formation of the Shh gradient
    The roles of Ptch1 and Disp1 in the formation of the Shh gradient
    The roles of Ptch1 and Disp1 in the formation of the Shh gradient
    海外基金