Difference between revisions of "Phosphatase Subfamily PTPRD"

Latest revision as of 21:42, 21 December 2016

Phosphatase Classification: Fold CC1: Superfamily CC1: Family PTP: Subfamily PTPRD

PTPRD phosphatases localize to axonal growth cones, regulating neuronal growth and guidance and participating in excitatory synapse formation and maintenance in vertebrates as well as invertebrates.

Evolution

PTPRD is found in holozoa (metazoa plus choanoflagellates). PTPRD has three members in human and most vertebrates: PTPRD, PTPRF and PTPRS. It has single member in most invertebrate metazoa but greatly expanded in sponge.

Domain Structure

All three human PTPRDs have twin intracellular PTP phosphatase domains, and extracellular Ig domains and FN3 domains. Each of them have multiple alternative splicing isoforms [1, 2, 3]. Invertebrate homologs have a similar architecture, though many gene models are incomplete.

Functions

PTPRF (LAR)

The best characterized member of the three human genes in the subfamily is PTPRF, aka LAR. Knock-down of PTPRF by siRNA induced post-receptor insulin resistance with the insulin-induced activation of PKB/Akt and MAP kinases markedly inhibited. But, the phosphorylation and dephosphorylation of the IR and insulin receptor substrate (IRS) proteins were unaffected by PTPRF knock-down [4].

PTPRF dephosphorylates tyrosine residues in both the C-terminus and kinase domain of Fyn in vitro. It binds to Fyn SH2 domain when its 2nd phosphatase was tyrosine phosphorylated by Fyn tyrosine kinase. In addition to Fyn kinase, PTPRF mutants, with Cys to Ser mutation in the catalytic center of 1st phosphatase domain, can bind to tyrosine-phosphorylated Lck kinase [5].

PTPRF dephosphorylates Death-associated protein kinase (DAPK) at pY491/492 to stimulate the catalytic, proapoptotic, and antiadhesion/antimigration activities of DAPK [6]. (Note: Upon EGF stimulation, a rapid Src activation leads to subsequent LAR downregulation.)

PTPRF targets to lipid rafts via the interaction with caveolin-1 [7].

PTPRF plays important roles in cell-cell communication. PTPRF localizes to cadherin-beta-catenin-based cellular junctions. Assembly and disassembly of these junctions are regulated by tyrosine phosphorylation. PTPRF dephosphorylates E-cadherin (epithelial cadherin) in vitro [8]. The ectopic expression of PTPRF inhibits epithelial cell migration by preventing phosphorylation and the increase in the free pool of beta-catenin [9].

PTPRF also specifically dephosphorylates and destabilizes BCAR1/p130Cas (breast cancer anti-estrogen resistance 1) and may play a role in regulating cell adhesion-mediated cell survival [10].

PTPRF is involved in the pathogenesis of insulin resistance by binding and dephosphorylating insulin receptor. Its overexpression in muscle causes insulin resistance [11]. PTPRF associates with and preferentially dephosphorylates the insulin receptor that was tyrosine phosphorylated by insulin stimulation. When replace cysteine residue at catalytic motif with serine at the 1st phosphatase domain, PTPRF fails to dephosphorylate insulin receptor, which indicates 1st domain carries out the activity []. Replacing cysteine with serine at the 2nd domain resulted in weaker association, which suggests the 2nd domain may play regulatory role [12, 13]. The dephosphorylation of insulin receptor leads to decreased phosphorylation of the adaptor protein IRS-1 and its downstream molecule Akt (also known as PKB).

PTPRF dephosphorylated EphA2 (ephrin type-A receptor 2) at phosphotyrosyl 930, uncoupling Nck1 from EphA2 and thereby attenuating EphA2-mediated cell migration [14].

PTPRF associates with c-Met, and purified PTPRF dephosphorylates tyrosine-phosphorylated c-Met in in vitro [15]. Other PTPs also have shown activities toward c-Met [16], and it is unclear whether c-Met is PTPRF's physiological substrate.

PTPRD (RPTPdelta, PTPδ)

Human PTPRD is a tumor suppressor that is frequently inactivated and mutated in glioblastoma and other human cancers. PTPRD dephosphorylates STAT3 Y705, a residue that must be phosphorylated for STAT3 to be active [17]. PTPRD loss can cause of aberrant STAT3 activation in gliomas [18]. Human PTPRD is also associated with restless legs syndrome [19], but the underlying mechanism is unclear. PTPRD interacts with MIM-B, a putative metastasis suppressor protein binding to actin [20]. It is not clear whether MIM-B is its substrate. The 2nd phosphatase domain of PTPRD can bind to inhibit the 1st phosphatase domain of PTPRS [21].

PTPRD is also involved in synaptic differentiation. It can bidirectionally induce pre- and postsynaptic differentiation of neurons by trans-synaptically binding to interleukin-1 receptor accessory protein (IL-1RAcP) and IL-1RAcP-like-1 (IL1RAPL1) in a splicing-dependent manner [22].

PTPRS (RPTPsigma/RPTPσ)

PTPRS reduce EGFR phosphorylation and therefore modulates signaling of the epidermal growth factor receptor in A431 cells [23]. Frequent deletion of PTPRS was found in head and neck cancers. PTPRS loss promoted EGFR/PI3K pathway activation, modulated resistance to EGFR inhibition, and strongly determined survival in lung cancer patients with activating EGFR mutations [24].

PTPRS-deficient mice exhibit neurological and neuroendocrine defects [25, 26]. PTPRS interacts with proteoglycans heparan sulfate proteoglycans (HSPGs) and chondroitin sulfate proteoglycans (CSPGs) through extracellular region. The proteoglycans exert opposing effects on neuronal extension by competing to control the oligomerization of PTPRS [27]. The proteoglycan switch is a putative target of rheumatoid arthritis therapy [28].

PTPRS is involved in the regulation of autophagy. Loss of PTPRS increases levels of cellular Phosphatidylinositol-3-phosphate (PtdIns3P) [29]. However, it is unclear whether PtdIns3P is its physiological substrate.

References

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2. O'Grady P, Krueger NX, Streuli M, and Saito H. Genomic organization of the human LAR protein tyrosine phosphatase gene and alternative splicing in the extracellular fibronectin type-III domains. J Biol Chem. 1994 Oct 7;269(40):25193-9. PubMed ID:7929208 | HubMed [OGrady94]
3. Endo N, Rutledge SJ, Opas EE, Vogel R, Rodan GA, and Schmidt A. Human protein tyrosine phosphatase-sigma: alternative splicing and inhibition by bisphosphonates. J Bone Miner Res. 1996 Apr;11(4):535-43. DOI:10.1002/jbmr.5650110415 | PubMed ID:8992885 | HubMed [Endo96]
4. Mander A, Hodgkinson CP, and Sale GJ. Knock-down of LAR protein tyrosine phosphatase induces insulin resistance. FEBS Lett. 2005 Jun 6;579(14):3024-8. DOI:10.1016/j.febslet.2005.04.057 | PubMed ID:15896785 | HubMed [Mander05]
5. Tsujikawa K, Ichijo T, Moriyama K, Tadotsu N, Sakamoto K, Sakane N, Fukada S, Furukawa T, Saito H, and Yamamoto H. Regulation of Lck and Fyn tyrosine kinase activities by transmembrane protein tyrosine phosphatase leukocyte common antigen-related molecule. Mol Cancer Res. 2002 Dec;1(2):155-63. PubMed ID:12496362 | HubMed [Tsujikawa02]
6. Hoogenraad CC, Feliu-Mojer MI, Spangler SA, Milstein AD, Dunah AW, Hung AY, and Sheng M. Liprinalpha1 degradation by calcium/calmodulin-dependent protein kinase II regulates LAR receptor tyrosine phosphatase distribution and dendrite development. Dev Cell. 2007 Apr;12(4):587-602. DOI:10.1016/j.devcel.2007.02.006 | PubMed ID:17419996 | HubMed [Wang07]
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9. Müller T, Choidas A, Reichmann E, and Ullrich A. Phosphorylation and free pool of beta-catenin are regulated by tyrosine kinases and tyrosine phosphatases during epithelial cell migration. J Biol Chem. 1999 Apr 9;274(15):10173-83. DOI:10.1074/jbc.274.15.10173 | PubMed ID:10187801 | HubMed [Muller99]
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20. Woodings JA, Sharp SJ, and Machesky LM. MIM-B, a putative metastasis suppressor protein, binds to actin and to protein tyrosine phosphatase delta. Biochem J. 2003 Apr 15;371(Pt 2):463-71. DOI:10.1042/BJ20021962 | PubMed ID:12570871 | HubMed [woodings03]
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30. Furlan G, Minowa T, Hanagata N, Kataoka-Hamai C, and Kaizuka Y. Phosphatase CD45 both positively and negatively regulates T cell receptor phosphorylation in reconstituted membrane protein clusters. J Biol Chem. 2014 Oct 10;289(41):28514-25. DOI:10.1074/jbc.M114.574319 | PubMed ID:25128530 | HubMed [furlan14]