Phosphatase Subfamily PTPN5 RR

Phosphatase Classification: Fold CC1: Superfamily CC1: Family PTP: Subfamily PTPN5_RR

PTPN5 is a tyrosine-specific phosphatase subfamily. It is characterized by a kinase interaction motif (KIM), which is regulated by the phosphorylation state of a serine within the motif. Human has three members: PTPN5/STEP, PTPN7/HePTP, PTPRR/PTP-SL. They all regulate the ERK pathway, but may have specific substrates. They are expressed in different tissues, particularly, abundant in spleen, thymus, and different parts of the brain.

Evolution

PTPN5 subfamily emerged in eumetazoan and duplicated in vertebrates but lost in nematode.

Domains

PTPN5 members have an N-terminal kinase interaction motif (KIM) (~16 aa) (note: is is the same with MKP's KIM?) and a C-terminal phosphatase domain.

KIM mediates an interaction with ERK MAP kinases and with p53. The KIM is a serine that can be phosphorylated by PKA. The phosphorylation state of this serine affects the binding between phosphatases to MAP kinases ERK and p53, therefore rapidly change the response to external stimuli.

Several PTPN5 crystal structures have been solved [1, 2, 3, 4]. An additional helix H0 was found in mouse PTPRR and human PTPN7. The H0 of mouse PTPRR supports the site of phosphorylation at Thr253 when PTP-SL/BR7 interacts with ERK2 or p38. But, the H0 of PTPRR and PTPN7 do not align with each other in structure, and PTPN5 does not have H0.

Besides KIM and phosphatase domain, the longest isoform of human PTPN5 has two proline-rich regions [5].

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 membranes. All the three are abundantly expressed in brain: PTPN5 is mainly expressed in striatum and nucleus accumbens, which are part of the basal ganglia; in contrast, PTPRR is mainly expressed in cerebellum; PTPN7 is most abundantly expressed in thyroid, spleen, a nd whole blood, and it is also expressed at a lower level in the striatum and nucleus accumbens .

All three human proteins act as physiological regulators of the ERK1/2 signaling pathway. For PTPN7 and PTPRR, upon their binding to ERK1/2, their N-terminal domains were phosphorylated by ERK1/2 at the same positions (which are occupied by different amino acid in PTPN5), whereas they dephosphorylated the regulatory phosphotyrosine residues of ERK1/2 and inactivated ERK1/2 [2, 4, 6]. The interactions between PTPN7 and ERK, and PTPRR and ERK are mediated by kinase interaction motif (KIM). A serine residue in the KIM is phosphorylated by PKA (cAMP-dependent protein kinase) and dephosphorylated by some serine phosphatase, which rapidly affect the ability of PTPN7 and PTPRR binding to ERK and p38, and change in response to external stimuli. Although PTPN5/STEP does not have the residues phoshorylated by ERK, it has the KIM domain and the serine phosphorylated by PKA in PTPN7 and PTPRR.

Drosophila PTP-ER also acts as a MAPK phosphatase downstream of ras.

PTPN5 (STEP)

PTPN5 is also termed as "striatum enriched phosphatase" (STEP), since it is highly enriched within the striatum relative to other brain areas [7]. 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 [8] and development of stress-related cognitive and morphological changes [9], and its abnormality is related to Alzheimer's dieases [10, 11] and schizophrenia [12] (controversial, though, e.g. see [13]). 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 [6].

• 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 [5].

• 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 [10, 11].

• PTPRA at its regulatory Tyr-789 [14].

PTPN7 (HePTP/LC-PTP)

PTPN7 is a cytoplasmic protein tyrosine phosphatase whose expression is induced by mitogenic stimuli. It is also called hematopoietic tyrosine phosphatase (HePTP) or leukocyte PTP (LC-PTP), because it is most abundantly expressed in spleen, thyroid, and whole blood cells (including T cells, B cells, mast cells and etc) [15, 16, 17]. It is also expressed in striatum and nucleus accumbens, ardrenal gland, small intestine but at the same level as spleen, thyroid and whole blood (GTEX).

PTPN7 regulates the activity and translocation [18] of the MAP kinases Erk and p38, but not JNK [19, 20, 21, 22], particularly in T cell antigen receptor (TCR) signaling [19, 23]. It binds Erk and p38 via a short, highly conserved motif in its N-terminal kinase interaction motfi (KIM) from 142 to 157. Association via the KIM results in an unusual, reciprocal interaction between the two proteins. First, Erk phosphorylates PTPN7 at residues Thr171 and Ser198 (Thr45 and Ser72 in the paper [2] Figure 3a). Second, HePTP dephosphorylates Erk at pTyr185. According to crystal structure, both reactions require significant conformational changes in both proteins [2, 3]. The mechanism is similar to that of PTPRR as well as ERK-specific MKPs [4]. (Note: The two phosphorylated site Thr171 and Ser198 are observed in PTPN7 and PTPRR but not PTPN5.)

PTPN7 is under continuous control by PKA (cAMP-dependent protein kinase) and a serine-specific phosphatase, probably PP1, in T-cells, through phosphorylation at Ser-149, which locates in KIM (142-157) mediates the binding between PTPN7 and ERK and p39. This phosphorylation can there rapidly affect the ability of PTPN7 to inhibit the ERK and p38 MAP kinases, and change in response to external stimuli [24].

PTPN7 is amplified and overexpressed in myeloid malignancies, which implies it may promote abnormal myeloid cell growth [25].

It is worthy pointing out that PTPN7 has PTP activity, although it has substitution at N replaced by D at KNRY motif.

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

PTPRR is mainly expressed in brain [26, 27, 28]. 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 [29]. PTPRR dephosphorylates ERKs:

• 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 331-346 (224-239 in [6]). The KIM is conserved Figure 13B in [6]. Ser338 (Ser231 in paper [30]) within KIM is phosphorylated by cAMP-dependent protein kinase A (PKA) is critical for binding to ERK1/2 [30]. The binding is required for phosphorylation of PTPRR (PTP-SL) by ERK1/2 at Thr361 (Thr253 in paper) [4, 6, 31, 32]. 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 [4] (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 [33]. But, there is no direct evidence that PTPRR dephosphorylates ERK5 on specific residues.

PTPRR also functions in cancer. Methylation of the PTPRR promoter has a role in metastasis and may be a biomarker of invasive cervical cancer [34]. It is also an early and frequent target of silencing in human colorectal tumorigenesis [35].

References

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Supplementary information

The position in this page is numbered by the sequences below:

>PTPN5 CC1:CC1:PTP:PTPN5_RR [Homo sapiens] MNYEGARSERENHAADDSEGGALDMCCSERLPGLPQPIVMEALDEAEGLQDSQREMPPPPPPSPPSDPAQKPPPRGAGSHSLTVRSSLCLFAASQFLLACGVLWFSGYGHIWSQNATNLVSSLLTLLKQLEPTAWLDSGTWGVPSLLLVFLSVGLVLVTTLVWHLLRTPPEPPTPLPPEDRRQSVSRQPSFTYSEWMEEKIEDDFLDLDPVPETPVFDCVMDIKPEADPTSLTVKSMGLQERRGSNVSLTLDMCTPGCNEEGFGYLMSPREESAREYLLSASRVLQAEELHEKALDPFLLQAEFFEIPMNFVDPKEYDIPGLVRKNRYKTILPNPHSRVCLTSPDPDDPLSSYINANYIRGYGGEEKVYIATQGPIVSTVADFWRMVWQEHTPIIVMITNIEEMNEKCTEYWPEEQVAYDGVEITVQKVIHTEDYRLRLISLKSGTEERGLKHYWFTSWPDQKTPDRAPPLLHLVREVEEAAQQEGPHCAPIIVHCSAGIGRTGCFIATSICCQQLRQEGVVDILKTTCQLRQDRGGMIQTCEQYQFVHHVMSLYEKQLSHQSPE

>PTPN7 CC1:CC1:PTP:PTPN5_RR [Homo sapiens] MVGKAWPLTHSQGTGPWAPEGHRREAADPWWQRQQAQEGRMQLGCAWVAARRGGGRKLASWSLLSPQRQTDRQTDSWQEAAWGPQLLQQTSWLSEPPLGPAPHLSMVQAHGGRSRAQPLTLSLGAAMTQPPPEKTPAKKHVRLQERRGSNVALMLDVRSLGAVEPICSVNTPREVTLHFLRTAGHPLTRWALQRQPPSPKQLEEEFLKIPSNFVSPEDLDIPGHASKDRYKTILPNPQSRVCLGRAQSQEDGDYINANYIRGYDGKEKVYIATQGPMPNTVSDFWEMVWQEEVSLIVMLTQLREGKEKCVHYWPTEEETYGPFQIRIQDMKECPEYTVRQLTIQYQEERRSVKHILFSAWPDHQTPESAGPLLRLVAEVEESPETAAHPGPIVVHCSAGIGRTGCFIATRIGCQQLKARGEVDILGIVCQLRLDRGGMIQTAEQYQFLHHTLALYAGQLPEEPSP

>PTPRR CC1:CC1:PTP:PTPN5_RR [Homo sapiens] MRRAVCFPALCLLLNLHAAGCFSGNNDHFLAINQKKSGKPVFIYKHSQDIEKSLDIAPQKIYRHSYHSSSEAQVSKRHQIVNSAFPRPAYDPSLNLLAMDGQDLEVENLPIPAANVIVVTLQMDVNKLNITLLRIFRQGVAAALGLLPQQVHINRLIGKKNSIELFVSPINRKTGISDALPSEEVLRSLNINVLHQSLSQFGITEVSPEKNVLQGQHEADKIWSKEGFYAVVIFLSIFVIIVTCLMILYRLKERFQLSLRQDKEKNQEIHLSPITLQPALSEAKTVHSMVQPEQAPKVLNVVVDPQGRGAPEIKATTATSVCPSPFKMKPIGLQERRGSNVSLTLDMSSLGNIEPFVSIPTPREKVAMEYLQSASRILTRSQLRDVVASSHLLQSEFMEIPMNFVDPKEIDIPRHGTKNRYKTILPNPLSRVCLRPKNVTDSLSTYINANYIRGYSGKEKAFIATQGPMINTVDDFWQMVWQEDSPVIVMITKLKEKNEKCVLYWPEKRGIYGKVEVLVISVNECDNYTIRNLVLKQGSHTQHVKHYWYTSWPDHKTPDSAQPLLQLMLDVEEDRLASQGRGPVVVHCSAGIGRTGCFIATSIGCQQLKEEGVVDALSIVCQLRMDRGGMVQTSEQYEFVHHALCLYESRLSAETVQ