Recent studies show that type II transmembrane serine proteases play important roles in diverse cellular activities and pathological processes. Their expression and functions in the central nervous system, however, are largely unexplored. In this study, we show that the expression of one such member, matriptase (MTP), was cell type-restricted and primarily expressed in neural progenitor (NP) cells and neurons. Blocking MTP expression or MTP activity prevented NP cell traverse of reconstituted basement membrane, whereas overexpression of MTP promoted it. The NP cell mobilization induced by either vascular endothelial growth factor or hepatocyte growth factor was also impaired by knocking down MTP expression. MTP acts upstream of matrix metalloproteinase 2 in promoting NP cell mobility. In embryonic stem cell differentiation to neural cells, MTP knockdown had no effect on entry of embryonic stem cells into the neural lineage. High MTP expression or activity, however, shifts the population dynamics from NP cells toward neurons to favor neuronal differentiation. This is the first report to demonstrate the direct involvement of type II transmembrane serine protease in NP cell function.

No abstract

Brain neural stem cells and transit amplifying cells in the subventricular zone (SVZ) of the lateral ventricles are in direct contact with the microvascular endothelium. The mechanisms/molecules of direct cell contact in the SVZ neurovascular niche are not fully understood. We previously showed that neural stem/progenitor (NS/P) cells induce brain endothelial signaling in direct cell contact through matriptase (MTP) on NS/P cell surface. In the present study, using pull-down and LC-MS/MS, we identified melanoma cell adhesion molecule (MCAM) the brain endothelial molecule that interacts with MTP. MCAM physically binds to the CUB domains of MTP and induces a chain of brain endothelial signaling including p38MAPK activation, GSK3β inactivation and subsequently β-catenin activation; none of these signaling events occurred when either MTP or MCAM is deleted. MTP-MCAM binding and induction of endothelial signaling were all sensitive to cholera toxin. Together, we identified key molecules that may represent a mechanism in neural stem cell vascular niche regulation.

No abstract

Knockdown of the suppression of tumorigenicity 14–encoding type II transmembrane serine protease matriptase (MTP) in neural stem/progenitor (NS/P) cells impairs cell mobility, response to chemo‐attractants, and neurovascular niche interaction. In the present study, we showed by Western blot that a portion of MTP can be detected in the mitochondrial fraction of mouse NS/P cells by immunostaining that it is co‐stained with the mitochondrial dye MitoTracker (Thermo Fisher Scientific, Waltham, MA, USA) inside the cells. Co‐immunoprecipitation showed that MTP is bound to the β subunit of mitochondrial F0F1–ATP synthase complex (ATP‐β). Cytoimmunofluorescence staining and an in situ proximity ligation assay further confirmed a physical interaction between MTP and ATP‐β. This interaction relied on the presence of both Cls/Clr urchin embryonic growth factor, bone morphogenic protein 1 and low‐density lipoprotein receptor motifs of MTP. We found that NS/P cell mitochondrial membrane potential is impaired by MTP knockdown, and ATP synthesis and oxygen consumption rate are significantly reduced in MTP‐knockdown NS/P cells. Among the oxidative phosphorylation functions, the greatest effect of MTP knockdown is the reduction by over 50% in the mitochondrial energy reserve capacity. This made MTP‐knockdown NS/P cells unable to overcome hydrogen peroxide stress, which leads to cessation of cell growth. This work identifies 2 previously unknown functions for MTP: first as a binding protein in the mitochondrial F1F0–ATP synthase complex and second as a regulatory mechanism of mitochondrial bioenergetics. Mitochondrial MTP may serve a protective function for NS/P cells in response to stress.—Fang, J.‐D., Tung, H.‐H., Lee, S.‐L. Mitochondrial localization of St14‐encoding transmembrane serine protease is involved in neural stem/progenitor cell bioenergetics through binding to F0F1–ATP synthase complex. FASEB J. 33,4327‐4340 (2019). http://www.fasebj.org