TMEM27: A Cleaved and Shed Plasma Membrane Protein That Stimulates Pancreatic Beta Cell Proliferation

Abstract

The signals and the molecular mechanisms that regulate the replication of terminally differentiated β cells are unclear. In this thesis I report the identification of a gene encoding transmembrane protein 27 (TMEM27) in pancreatic β cells. Expression of Tmem27 is reduced in Tcf1–/– mice, which exhibit defects in proliferation, and is increased in islets of ob/ob, db/db and aP2- Srebp-1c transgenic mice with marked hypertrophy of the endocrine pancreas. Tmem27 is expressed in hormone positive cells at early stages of pancreas development and becomes restricted to pancreatic β cells in the mature pancreas. Biochemical characterization revealed that the Tmem27 exists as a dimer and that its extracellular domain is glycosylated, cleaved and shed from the plasma membrane. The cleavage process of Tmem27 is β cell-specific and does not occur in other cell types. Overexpression of full-length Tmem27, but not the truncated or soluble protein, in MIN6 cells leads to increased thymidine incorporation, whereas silencing of Tmem27 using RNAi results in a reduction of cell replication. Furthermore, transgenic mice with increased expression of Tmem27 in pancreatic β cells exhibit increased β cell mass compared to their control littermates. The following results identify a novel pancreatic β cell-shed protein that regulates cell growth of pancreatic islets.