An Shp2/SFK/Ras/Erk Signaling Pathway Controls Trophoblast Stem Cell Survival

Abstract

Little is known about how growth factors control tissue stem cell survival and proliferation. We analyzed mice with a null mutation of Shp2 (Ptpn11), a key component of receptor tyrosine kinase signaling. Null embryos die peri-implantation, much earlier than mice that express an Shp2 truncation. Shp2 null blastocysts initially develop normally, but they subsequently exhibit inner cell mass death, diminished numbers of trophoblast giant cells, and failure to yield trophoblast stem (TS) cell lines. Molecular markers reveal that the trophoblast lineage, which requires fibroblast growth factor-4 (FGF4), is specified but fails to expand normally. Moreover, deletion of Shp2 in TS cells causes rapid apoptosis. We show that Shp2 is required for FGF4-evoked activation of the Src/Ras/Erk pathway that culminates in phosphorylation and destabilization of the proapoptotic protein Bim. Bim depletion substantially blocks apoptosis and significantly restores Shp2 null TS cell proliferation, thereby establishing a key mechanism by which FGF4 controls stem cell survival.

Shp2/MAPK signaling controls goblet/paneth cell fate decisions in the intestine

“…In mice, a null mutation of Shp2 interfered with the expansion of the trophoblast cell lineage and led to implantation deficits (15). Shp2 is also required for the development and maintenance of the nervous system, the kidney, and other organs (13,14,16,17); its role in the maintenance of the intestinal epithelium is not fully investigated.…”

Protein tyrosine phosphatase activity in the neural crest is essential for normal heart and skull development

“…SHP2 is essential for early vertebrate development and can regulate cell migration, proliferation, survival, and differentiation through pathways, including the MAPK, ERK1/2 branch (7). Mice homozygous for a null mutation in PTPN11 die at implantation due to failure in the development of the extraembryonic trophoectodermal lineage, whereas induction of a dominant-negative SHP2 in Xenopus blocks mesoderm formation by impairing ERK signaling, leading to arrest of gastrulation (8,9).…”

Noonan Syndrome/Leukemia-associated Gain-of-function Mutations in SHP-2 Phosphatase (PTPN11) Enhance Cell Migration and Angiogenesis

“…Homozygous deletion of Exon 2 (4) or Exon 3 (5) of the SHP-2 gene (PTPN11) in mice leads to early embryonic lethality prior to and at midgestation, respectively. SHP-2 null mutant mice die much earlier, at peri-implantation (4).…”

“…Homozygous deletion of Exon 2 (4) or Exon 3 (5) of the SHP-2 gene (PTPN11) in mice leads to early embryonic lethality prior to and at midgestation, respectively. SHP-2 null mutant mice die much earlier, at peri-implantation (4). Exon 3 deletion mutation of SHP-2 blocks hematopoietic potential of embryonic stem cells both in vitro and in vivo (6 -8), whereas SHP-2 null mutation causes inner cell mass death and diminished trophoblast stem cell survival (4).…”

“…SHP-2 null mutant mice die much earlier, at peri-implantation (4). Exon 3 deletion mutation of SHP-2 blocks hematopoietic potential of embryonic stem cells both in vitro and in vivo (6 -8), whereas SHP-2 null mutation causes inner cell mass death and diminished trophoblast stem cell survival (4). Recent studies on SHP-2 conditional knock-out or tissue-specific knock-out mice have further revealed an array of important functions of this phosphatase in various physiological processes (9 -12).…”