The Role of SHP-2 in Cell Signalling and Human Disease

Hanna      Mannell; Florian      Krotz

Abstract

The activation and transduction of several signalling pathways are dependent on tyrosine phosphorylation. The non-transmembrane protein tyrosine phosphatase SHP-2 (Src homology 2 domain containing tyrosine phosphatase 2) has been shown to be involved in several signalling pathways initiated by different growth factors, cytokines, hormones and extracellular matrix receptors. SHP-2 directly interacts with several growth factors, cell surface adhesion molecules and different adaptor molecules such as the Grb 2 associated binder 1 (Gab-1), Grb2 and the insulin receptor substrate 1 (IRS- 1). It has been shown to be required for activation of the mitogen activated protein kinase (MAP-Kinase) pathway upon fibroblast growth factor (FGF), epidermal growth factor (EGF) and insulin stimulation. Moreover, SHP-2 has been found to influence the phosphoinositide 3-Kinase (PI3-Kinase)/kt pathway upon stimulation with EGF, insulin like growth factor (IGF) and platelet derived growth factor (PDGF), thus affecting cell survival. SHP-2 also plays a negative role in certain signalling pathways, such as the janus activated kinase (JAK)-signal transducers and activators of transcription (STAT) pathway. Recently, SHP-2 has become clinically relevant as germ-line missense mutations in the gene encoding SHP-2 (Ptpn11) have been found to cause the developmental disorders Noonan syndrome and the Leopard syndrome. Other mutations in this gene lead to myeloid and lymphoid malignancies. Moreover, SHP-2 has also been implicated to play a role in diabetes and in the development of gastric adenocarcinoma following H. Pylori infection. This article deals with the role of SHP-2 in different signalling pathways and the involvement of SHP-2 in human disorders.

Keywords: SHP-2, protein tyrosine phosphatase, Noonan syndrome, PI3-Kinase, MAP-Kinase, tyrosine phosphorylation, PTP, N-SH2