Phosphatase Subfamily PTPN5 RR

Phosphatase Classification: Fold CC1: Superfamily CC1: Family PTP: Subfamily PTPN5

Domain Structure

The longest isoform of human PTPN5 has an extracellular region containing proline-rich domain, a transmembrane region, a cytoplasmic region containing another proline-rich domain, a kinase interaction motif (KIM), and a phosphatase domain [1].

Functions

Human has three members: PTPN5, PTPN7 and PTPRR. Though PTPN5 and PTPN7 are named as non-receptor PTPs, at least some of their isoforms contain predicted transmembrane region or have been show to associate with membrane. All the three are abundantly expressed in brain but in different parts. PTPN5 and PTPN7 is mainly expressed in striatum and nucleus accumbens, which are part though not all of basal ganglia; in contrast, PTPRR is mainly expressed in cerebellum.

PTPN5/STEP and PTPRR/PTP-SL act as physiological regulators of the ERK1/2 signaling pathway. Upon PTPN5 and PTPRR binding to ERK1/2, their N-terminal domains were phosphorylated by ERK1/2, whereas they dephosphorylated the regulatory phosphotyrosine residues of ERK1/2 and inactivated ERK1/2 [2].

PTPN5 (STEP)

PTPN5 is also termed as "striatum enriched phosphatase" (STEP), since it is highly enriched within the striatum relative to other brain areas [3]. This expression pattern is consistent with GTEx. PTPN5 is most abundantly expressed in striatum (including caudate and putamen) and nucleus accumbens, which are part though not all of basal ganglia. It is not surprised that PTPN5 is related to long-term memories, neuroplasticity [4] and development of stress-related cognitive and morphological changes [5], and its abnormality is related to Alzheimer's dieases [6, 7] and schizophrenia [8]. PTPN5 has 6 isoforms in Entrez database, which may have different functions. In particular, it is named as non-receptor PTP, but some of its isoforms have predicted transmembrane region. PTPN5 have various substrates, including:

• ERK1/2 as shown above [2].

• Fyn, a kinase of Src family. PTPN5 also regulates the activity of Fyn kinase by specifically dephosphorylating the regulatory Tyr420 but not at Tyr531. A membrane-associated isoform of PTPN5, STEP(61), located in the postsynaptic densities (PSDs) of striatal neurons. STEP(61) associates with Fyn which is also enriched in PSDs. A substrate-trapping variant (STEP(61) CS) binds to Fyn but not to other members of the Src family present in PSDs. STEP(61) binds to Fyn through one of its proline-rich domains and the kinase-interacting motif domain, whereas Fyn binds to STEP(61) through its Src homology 2 domain and the unique N-terminal domain [1].

• NR2B, NMDA receptor subunit. PTPN5 dephoshorylates NMDA receptor subunits and increases NMDA receptor endocytosis, which may contribute to the cognitive deficits in Alzheimer's disease. Amyloid beta mediate the accumulation of STEP(61), dephosphorylation of Tyr1472 of the NR2B subunit, and decreased NR1 and NR2B subunits on neuronal membranes. The underlying mechanism is unclear, but perhaps related to the ubiquitin proteasome system [6, 7].

PTPRR (EC-PTP/PTP-SL/PTPBR7)

PTPRR is mainly expressed in brain [9, 10, 11]. In particular, according to GTEx, it is most abundantly expressed in cerebellum (cerebellum and cerebellar hemisphere in GTEx); it is also expressed in other parts of brain but at lower level. Besides brain, PTPRR is also expressed in uterus, bladder, and traverse colon (interestingly not sigmoid colon). Like PTPN5, PTPRR has multiple isoforms, each of which has a unique expression pattern in specific cell populations as well as in tissue regions as shown in mouse [12].

• ERK1/2. A sequence of 16 amino acids in PTPRR/PTP-SL was identified as being critical for ERK1/2 binding and termed kinase interaction motif (KIM) at 224-239 (331-346 in the sequences in phosphatome.net database). The KIM is conserved Figure 13B in [2]. Ser231 (Ser338 in phosphatome.net sequence) within KIM is phosphorylated by cAMP-dependent protein kinase A (PKA) is critical for binding to ERK1/2 [13]. The binding is required for phosphorylation of PTPRR (PTP-SL) by ERK1/2 at Thr253 (Thr361 in PTPRR's sequence in phosphatome.net database) [2, 14, 15, 16]. Based upon crystal structure of PTPRR-ERK2 complex, the subsequent dephosphorylation of ERK2 seems to be possible only if a conformational rearrangement of the two interacting partners takes place [16] (Note 1:. this is similar to MKP of DSP family). (Note 2: The KIM locates at PTPN5:238-253, PTPN7:142-157, PTPRR:331-346, according to the sequences in phosphatome.net database. The phosphorylated Thr361 is not conserved, which aligned to Thr171 in PTPN7 but Ser268 in PTPN5.)

• ERK5? PTPRR can bind to ERK5, down-regulate endogenous ERK5 activity, and impede the translocation of ERK5 to the nucleus. On the other hand, PTPRR is a substrate of ERK5 and independent of phosphorylation binding to the kinase enhances its catalytic phosphatase activity [17]. But, there is no direct evidence that PTPRR dephosphorylates ERK5 on specific residues.

PTPRR also functions in cancer. Methylation of the PTPRR promoter has an important role in the metastasis and may be a biomarker of invasive cervical cancer [18]. It is also an early and frequent target of silencing in human colorectal tumorigenesis [19].

References

1. Nguyen TH, Liu J, and Lombroso PJ. Striatal enriched phosphatase 61 dephosphorylates Fyn at phosphotyrosine 420. J Biol Chem. 2002 Jul 5;277(27):24274-9. DOI:10.1074/jbc.M111683200 |
2. Pulido R, Zúñiga A, and Ullrich A. PTP-SL and STEP protein tyrosine phosphatases regulate the activation of the extracellular signal-regulated kinases ERK1 and ERK2 by association through a kinase interaction motif. EMBO J. 1998 Dec 15;17(24):7337-50. DOI:10.1093/emboj/17.24.7337 |
3. Lombroso PJ, Murdoch G, and Lerner M. Molecular characterization of a protein-tyrosine-phosphatase enriched in striatum. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7242-6. DOI:10.1073/pnas.88.16.7242 |
4. Olausson P, Venkitaramani DV, Moran TD, Salter MW, Taylor JR, and Lombroso PJ. The tyrosine phosphatase STEP constrains amygdala-dependent memory formation and neuroplasticity. Neuroscience. 2012 Dec 6;225:1-8. DOI:10.1016/j.neuroscience.2012.07.069 |
5. Yang CH, Huang CC, and Hsu KS. A critical role for protein tyrosine phosphatase nonreceptor type 5 in determining individual susceptibility to develop stress-related cognitive and morphological changes. J Neurosci. 2012 May 30;32(22):7550-62. DOI:10.1523/JNEUROSCI.5902-11.2012 |
6. Kurup P, Zhang Y, Xu J, Venkitaramani DV, Haroutunian V, Greengard P, Nairn AC, and Lombroso PJ. Abeta-mediated NMDA receptor endocytosis in Alzheimer's disease involves ubiquitination of the tyrosine phosphatase STEP61. J Neurosci. 2010 Apr 28;30(17):5948-57. DOI:10.1523/JNEUROSCI.0157-10.2010 |
7. Zhang Y, Kurup P, Xu J, Anderson GM, Greengard P, Nairn AC, and Lombroso PJ. Reduced levels of the tyrosine phosphatase STEP block β amyloid-mediated GluA1/GluA2 receptor internalization. J Neurochem. 2011 Nov;119(3):664-72. DOI:10.1111/j.1471-4159.2011.07450.x |
8. Pelov I, Teltsh O, Greenbaum L, Rigbi A, Kanyas-Sarner K, Lerer B, Lombroso P, and Kohn Y. Involvement of PTPN5, the gene encoding the striatal-enriched protein tyrosine phosphatase, in schizophrenia and cognition. Psychiatr Genet. 2012 Aug;22(4):168-76. DOI:10.1097/YPG.0b013e3283518586 |
9. Sharma E and Lombroso PJ. A neuronal protein tyrosine phosphatase induced by nerve growth factor. J Biol Chem. 1995 Jan 6;270(1):49-53. DOI:10.1074/jbc.270.1.49 |
10. Sharma E and Lombroso PJ. A neuronal protein tyrosine phosphatase induced by nerve growth factor. J Biol Chem. 1995 Jan 6;270(1):49-53. DOI:10.1074/jbc.270.1.49 |
11. Shiozuka K, Watanabe Y, Ikeda T, Hashimoto S, and Kawashima H. Cloning and expression of PCPTP1 encoding protein tyrosine phosphatase. Gene. 1995 Sep 11;162(2):279-84. DOI:10.1016/0378-1119(95)00306-q |
12. Augustine KA, Silbiger SM, Bucay N, Ulias L, Boynton A, Trebasky LD, and Medlock ES. Protein tyrosine phosphatase (PC12, Br7,S1) family: expression characterization in the adult human and mouse. Anat Rec. 2000 Mar 1;258(3):221-34. DOI:10.1002/(SICI)1097-0185(20000301)258:3<221::AID-AR1>3.0.CO;2-W |
13. Blanco-Aparicio C, Torres J, and Pulido R. A novel regulatory mechanism of MAP kinases activation and nuclear translocation mediated by PKA and the PTP-SL tyrosine phosphatase. J Cell Biol. 1999 Dec 13;147(6):1129-36. DOI:10.1083/jcb.147.6.1129 |
14. Ogata M, Oh-hora M, Kosugi A, and Hamaoka T. Inactivation of mitogen-activated protein kinases by a mammalian tyrosine-specific phosphatase, PTPBR7. Biochem Biophys Res Commun. 1999 Mar 5;256(1):52-6. DOI:10.1006/bbrc.1999.0278 |
15. Zúñiga A, Torres J, Ubeda J, and Pulido R. Interaction of mitogen-activated protein kinases with the kinase interaction motif of the tyrosine phosphatase PTP-SL provides substrate specificity and retains ERK2 in the cytoplasm. J Biol Chem. 1999 Jul 30;274(31):21900-7. DOI:10.1074/jbc.274.31.21900 |
16. Szedlacsek SE, Aricescu AR, Fulga TA, Renault L, and Scheidig AJ. Crystal structure of PTP-SL/PTPBR7 catalytic domain: implications for MAP kinase regulation. J Mol Biol. 2001 Aug 17;311(3):557-68. DOI:10.1006/jmbi.2001.4890 |
17. Buschbeck M, Eickhoff J, Sommer MN, and Ullrich A. Phosphotyrosine-specific phosphatase PTP-SL regulates the ERK5 signaling pathway. J Biol Chem. 2002 Aug 16;277(33):29503-9. DOI:10.1074/jbc.M202149200 |
18. Su PH, Lin YW, Huang RL, Liao YP, Lee HY, Wang HC, Chao TK, Chen CK, Chan MW, Chu TY, Yu MH, and Lai HC. Epigenetic silencing of PTPRR activates MAPK signaling, promotes metastasis and serves as a biomarker of invasive cervical cancer. Oncogene. 2013 Jan 3;32(1):15-26. DOI:10.1038/onc.2012.29 |
19. Menigatti M, Cattaneo E, Sabates-Bellver J, Ilinsky VV, Went P, Buffoli F, Marquez VE, Jiricny J, and Marra G. The protein tyrosine phosphatase receptor type R gene is an early and frequent target of silencing in human colorectal tumorigenesis. Mol Cancer. 2009 Dec 16;8:124. DOI:10.1186/1476-4598-8-124 |