Abstract
SH2 domain-containing tyrosine phosphatase-2 (PTPN11 or Shp2) is a ubiquitously expressed protein that plays a key regulatory role in cell proliferation, differentiation and growth factor (GF) signaling. This enzyme is well expressed in various retinal neurons and has emerged as an important player in regulating survival signaling networks in the neuronal tissues. The non-receptor phosphatase can translocate to lipid rafts in the membrane and has been implicated to regulate several signaling modules including PI3K/Akt, JAK-STAT and Mitogen Activated Protein Kinase (MAPK) pathways in a wide range of biochemical processes in healthy and diseased states. This review focuses on the roles of Shp2 phosphatase in regulating brain-derived neurotrophic factor (BDNF) neurotrophin signaling pathways and discusses its cross-talk with various GF and downstream signaling pathways in the retina.
Highlights
Src homology 2 (SH2) domain-containing tyrosine phosphatase-2 (Shp2) is a 593 amino acid non-transmembrane protein tyrosine phosphatase (PTP) encoded by PTPN11 gene (He et al, 2014)
Regulates brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) signaling in Retinal ganglion cells (RGCs) Plays a critical role in maturation and function of Muller cells which is required for retinal neuron survival; positively regulates Ras-Extracellular signal-regulated kinases (ERK) signaling in retinal survival Initiation of retinal neurogenesis; controls optic vesicle patterning; mediating Ras-FGF signaling Promotes photoreceptor differentiation Retinal and lens development through FGF signaling Recruited by Myelin-associated glycoprotein (MAG)-induced Paired immunoglobulin-like receptor B (PIR-B) receptor and regulates PIR-B related pathways in neurons; promotes inhibition of neurite growth Regulates brain immunoglobulin-like molecule (BIT) phosphorylation which is involved in neural transmission in the retina Early development of lens and retina through signaling Plays an essential role in photoreceptor signaling pathways by regulating growth factor (GF)-associated downstream signals
SH2 domain-containing tyrosine phosphatase-2 (Shp2) ablation, in photoreceptors was shown to stimulate STAT3 activation which might either suggest the regulatory role of phosphatase in photoreceptors survival pathway or be an injury dependant response protecting the retina from further profound injury caused by ERK downregulation
Summary
SH2 domain-containing tyrosine phosphatase-2 (Shp2) is a 593 amino acid non-transmembrane protein tyrosine phosphatase (PTP) encoded by PTPN11 gene (He et al, 2014). Dysfunction of Muller glial cells due to genetic disruption of Shp may indirectly affect other retinal neurons such as photoreceptors and RGCs leading to retinal neuronal death and degeneration (Joly et al, 2008; Bringmann et al, 2009) This fact is due to the neuroprotective support that Muller cells provide to the whole retina potentially by producing neuroprotective factors such as BDNF that enhance neuroprotective survival signaling through Extracellular signal-regulated kinases (ERK) and Akt pathway activation (Bringmann et al, 2009; Table 1). Act in a Ras-MAPK dependent signaling pathway (Cai et al, 2010, 2011; Table 1) Functions of this phosphatase in sustained activation of Ras/ ERK signaling effectors and its positive involvement in BDNF/TrkB-promoting survival effects on PC12 cells and on cultured cerebral and ventral mesencephalic neurons have previously been reported (Neel et al, 2003; Zhang et al, 2004). The role of other significant caveolar proteins such as Cavin family members polymerase I and transcript release factor (PTRF) which participate in caveolae formation through its interaction with Cav-1, have not been extensively investigated
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