State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
Cell Rep. 2022 Mar 22;38(12):110548. doi: 10.1016/j.celrep.2022.110548.
The protein C receptor (Procr) has been implicated as a stem cell surface marker in several tissues. It is unknown whether Procr acts as a functional signaling receptor in stem cells. Here, by conditional knockout in mammary stem cells (MaSCs), we demonstrate that Procr is essential for mammary gland development and homeostasis. Through proteomics profiling, we identify that, upon stimulation by the ligand protein C, Procr interacts with heat shock protein 90 (HSP90AA1) via its short cytoplasmic tail, recruiting Src and IGF1R to the complex at the plasma membrane. We show that Procr acts as a signaling receptor of protein C in regulation of MaSCs through HSP90, Src, and IGF1R in vitro. In vivo, IGF1R deletion in MaSCs displays similar phenotypes to Procr deletion. These findings illustrate the essential role of Procr signaling in MaSC maintenance, shedding light onto the molecular regulation by Procr in tissue stem cells.
蛋白 C 受体（Procr）已被发现在几种组织中作为干细胞表面标志物。目前尚不清楚 Procr 是否在干细胞中作为功能性信号受体发挥作用。在这里，通过在乳腺干细胞（MaSCs）中条件性敲除，我们证明 Procr 对于乳腺发育和稳态是必需的。通过蛋白质组学分析，我们发现，在配体蛋白 C 的刺激下，Procr 通过其短的细胞质尾巴与热休克蛋白 90（HSP90AA1）相互作用，将Src 和 IGF1R 募集到质膜上的复合物中。我们表明，Procr 在 MaSCs 中的作用是作为蛋白 C 的信号受体，通过 HSP90、Src 和 IGF1R 在体外调节 MaSCs。在体内，MaSCs 中 IGF1R 的缺失显示出与 Procr 缺失相似的表型。这些发现说明了 Procr 信号在 MaSC 维持中的重要作用，揭示了 Procr 在组织干细胞中的分子调控作用。
