Phosphatase Subfamily PTPN12

Phosphatase Classification: Fold CC1:Superfamily CC1: Family PTP: Subfamily PTPN12

Evolution

PTPN12 emerged in holozoa and is duplicated in vertebrates, but is lost in ecdysozoa.

Domain Architecture

PTPN12 subfamily has a N-terminal phosphatase domain (crystal structure see [1]) and a C-terminal region containing several proline-rich sequences, which mediate their interactions with SH3-domain-containing proteins. The region of 301-320 in PTPN22 interacts with its phosphatase domain and reduces its catalytic activity [2].

Functions

PTPN12 has three human members, PTPN12 (PTP-PEST, PTP-G1), PTPN18 (BDP), and PTPN22 (LYP). They have different functions, though they share some common interacting partners and substrates.

PTPN12 (PTP-PEST/PTPG1)

PTPN12 is widely expressed in different tissues and at relatively low level in brain according to GTEx [3, 4, 5].

PTPN12 has the following substrates and/or interacting partners involved in lymphocyte activation, cytoskeleton organization etc.

• p130Cas/BCAR1 [6]. p130Cas/BCAR1 is an adaptor protein that regulates multiple signaling pathways and implicated in cancers. PTPN12 interacts with p130Cas/BCAR1 via its proline-rich sequences on C-terminus and SH3 domain of p130Cas/BCAR1. Furthermore, PTPN12 dephosphorylates p130Cas/BCAR1, therefore terminating tyrosine phosphorylation-dependent signalling events downstream of p130cas [7, 8]. PTPN12 also interacts with other members of the p130(Cas) family (Hef1 and Sin) via their SH3 domain in vitro [9].

• PSTPIP1/CD2BP1 and PSTPIP2 (Proline-serine-threonine phosphatase-interacting protein 1 and 2). PTPN12 interacts with and dephosphorylates the two proteins. The interactions are mediated by C-terminal region of PTPN12 [10, 11, 12, 13, 14]. PTPN12 dephosphorylates Tyr-344 of PSTPIP1 and prevents its interaction with SH2 domain-containing proteins [15].

• WASP. WASP is involved in the transduction of signals from receptors on the cell surface to the actin cytoskeleton. PTPN12 can dephosphorylate WASP on Tyr-291. PTPN12 does not interact with WASP, directly; Instead, PTPN12 interacts with PSTPIP, which form a complex with WASP [15].

• c-Abl. c-Abl is a proto-oncogene encoding cytoplasmic and nuclear protein tyrosine kinase (ABL family in KinBase). It is implicated in processes of cell differentiation, cell division, cell adhesion, and stress response. PTPN12 interacts with and dephosphorylates c-Abl via PSTPIP1. On the other hand, c-Abl phosphorylates PSTPIP1 [16].

• PYK2/PTK2B/CADTK/RAFTK/CAKbeta. PTPN12 dephosphorylates PYK2 at its major autophosphorylation site Tyr-402 and activation loop tyrosine residues, Tyr-579 and Tyr-580. The other FAK kinase family member, Fak, is a poor PTPN12 substrate [17]. Both PYK2 and FAK colocalize with, bind to, and induce tyrosine phosphorylation of p130Cas and paxillin, which are also substrates of PTPN12.

• Insulin receptor (InsR). InsR is a receptor tyrosine kinase that plays a key role in the regulation of glucose homeostasis [18].

• CTNND1/p120Cas, a gene functions in adhesion between cells and signal transduction. PTPN12 dephosphorylates p120Cas at Y335 in the N-terminal domain [19].

• Paxilin, an adaptor protein is a substrate and interacting partner of PTPN12 [20, 21]. It has a N-terminal paxilin domain and C-terminal four LIM domains. The interaction is mediated by proline-rich region of PTPN12 and LIM3 and LIM4 of paxilin [22].

• HIC-5/TGFB1I1, paxilin homolog. HIC-5/TGFB1I1 has the same domain combination as paxilin, N-terminal paxilin domain and C-terminal four tandem LIM domains. PTPN12 binds to HIC-5 via its proline-rich sequence the 3rd LIM domain (LIM3) of HIC-5 [23].

• STAT3? PTPN12 was associated with STAT3 and induced STAT3 dephosphorylation. However, it is unclear whether it is by direct phosphorylation [24].

• SHC1, SHC-transforming protein 1. SHC encodes three adaptor proteins, p66, p52, p46, transmit signaling of the cell surface receptors such as EGFR, erbV-2 and insulin receptors. The isoforms are different in domain combination and functions (domain combination picture and text). PTPN12 interacts with p66 and p52 but not p46, which suggest the interaction is mediated by the C-terminal region of CH2 domain common in p66 and p52 but absent from p46 [25]. However, another study in mouse found the interaction between PTPN12 and SHCp52 was mediated by SHCp52 PTB domain and NPLH sequence in the C-terminus of murine PTPN12 [26]. (note: synergy between PTB and CH2 domain?) The interaction is stimulated by activators of protein kinase C (PKC) [25].

• Cyclic AMP-dependent protein kinase (PKA) and protein kinase C (PKC) regulates PTPN12 via phosphorylation at Ser-39 and Ser-435. Phosphorylation of Ser-39 in vitro decreases the phosphatase activity of by reducing its affinity for substrate [27].

• PPP1CA/PP1 catalytic subunit, alpha isozyme]. PPP1C associates with PTPN12 C-terminal region (proline-rich sequence?) and dephosphorylates PTPN12 at pSer-9, which is phosphorylated by PKA [28].

• ERK1/2 phosphorylate PTPN12 at Serine-571 [29].

• Adaptor molecule Grb2 binds to PTPN12 via two SH3 domains of Grb2 and proline-rich sequences of PTPN12. The interaction couples PTPN12 with growth factor receptors [30].

• Gelsolin, an actin-binding protein that is a key regulator of actin filament assembly and disassembly [31].

• Leupaxin forms a signaling complex with PTPN12, Pyk2, and c-Src to regulate migration of prostate cancer cells [32].

• Caspase 3 specifically cleaves PTPN12 at the (549)DSPD motif and therefore regulates PTPN12 interactions with paxillin, leupaxin, Shc, and PSTPIP [33].

• PIN1 (Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1) [29]

• JAK2 [34]

PPTN12 is implicated in cancer [24, 35, 36, 37, 38, 39, 40, 41], particularly in regulating cell motility.

PTPN18 (BDP1/PTP-HSCF)

PTPN18 was first identified as Brain Derived Phosphatase (BDP1) [42]. According RNA-seq data from GTEx, PTPN18 is most abundantly expressed in spleen. In brain, it is most abundant in cerebellum at similar level with whole blood, small intestine, prostate and transverse colon. Its expression in other parts of brain is much lower in comparison with the tissues above.

PTPN18 have below substrates and/or interacting partners:

• PSTPIP1 and PSTPIP2 (Proline-serine-threonine phosphatase-interacting protein 1 and 2). PTPN18 interacts with and dephosphorylates the two proteins. The interactions are mediated by C-terminal region of PTPN18 [10, 11, 12].

• c-Abl. c-Abl is a proto-oncogene encoding cytoplasmic and nuclear protein tyrosine kinase (ABL family in KinBase). It is implicated in processes of cell differentiation, cell division, cell adhesion, and stress response. PTPN18 interacts with and dephosphorylates c-Abl via PSTPIP1. On the other hand, c-Abl phosphorylates PSTPIP1 [16].

• CSK. Like PTPN12 and PTPN22, PTPN18 interacts with CSK. However, the interaction is not mediated by CSK SH3 domain, instead by CSK SH2 domain [43].

• HER2/ErbB2 PTPN18 is a negative regulator of HER2/ErbB2 [44] but it is unclear whether it ErbB2 is a direct substrate.

PTPN22 (LYP/PEP/PTPN8)

PTPN22 functions predominantly in hematopoietic tissues

Human PTPN22 (aka lymphoid tyrosine phosphatase, LYP) mainly functions in the immune system, and its R620W variant is associated with many autoimmune diseases. PTPN22 is expressed in certain tissues and cell types, including EBV-transformed lymphocytes, whole blood, spleen and small intestine - terminal ileum (GTEx). Northern blot analysis found PTPN22 to be expressed predominantly in hematopoietic tissue, including spleen, lymph node, thymus, peripheral blood leukocytes, bone marrow, and fetal liver [45, 46].

Human PTPN22 has several described functions:

• In T cells, PTPN22 negatively regulates T cell receptor (TCR) signaling [47].
• In myeloid cells, PTPN22 modulates TLR and possibly TNFR signaling by interacting with TRAF3 to augment activating lysine 63-linked ubiquitination and thus increase IRF3 and IRF7 activation and type I IFN production [47].
• PTPN22 is expressed in macrophages and plays a critical role in regulating macrophage activation and polarization [48].

R620W variant associated with multiple autoimmune diseases

Missense single-nucleotide polymorphism (SNP) R620W is associated with different autoimmune diseases [49, 50, 51, 52], including rheumatoid arthritis (RA) [53, 54, 55, 56], systemic lupus erythematosus (SLE) [55, 57, 58], type 1 diabetes (T1D) [49], Hashimoto thyroiditis [49], juvenile idiopathic arthritis (JIA) [59], Grave's disease (GD) [59]. However, multiple sclerosis (MS) did not show association with R620W [49].

PTPN22 R620W variant is associated with reduced activation, proliferation and IL-2 production in CD4(+)T cells among T1D patients, and PTPN22 R620W has higher catalytic activity and is a more potent negative regulator of T lymphocyte activation [60, 61]. Thus, R620W is a gain-of-function mutant.

One model behind is as following. R620 locates in a proline-rich sequence in PTPN22, which mediates the interaction between PTPN22 and tyrosine kinase CSK. The R620W variation disrupts not only the interaction between PTPN22 and CSK, but also that between PTPN22 and PTPN22's substrate Src kinase Lck, since PTPN22 constitutively interacts with Lck in a CSK-dependent manner. Lck is not only the substrate of PTPN22, but also phosphorylates PTPN22 at Tyr-536, playing an inhibitory role on the phosphatase activity [62]. Thus, the R620W variation disrupts the interaction between PTPN22 and Lck, leading to reduced phosphorylation at Tyr-536 of PTPN22, which ultimately contributes to gain-of-function inhibition of T cell signaling [62].

In normal, PTPN22 controls virally-induced autoimmune diabetes by modulating cytotoxic T lymphocyte responses in an epitope-specific manner [63].

Substrates and interacting partners

• Lck (lymphocyte-specific protein tyrosine kinase), a protein found inside specialized cells of the immune system called lymphocytes. Native PTPN22 dephosphorylated Lck at its activating tyrosine residue Tyr-394, but not at the regulatory tyrosine Tyr-505 [64]. On the other hand, Lck phosphorylates PTPN22 at Tyr-536, playing an inhibitory role on the phosphatase activity [62]. Lck is a member of TK group, Src family and SrcB subfamily according to KinBase. Other members in SrcB include LYN, BLK and HCK (note: can they be PTPN22's substrates?).

• ZAP70 (Zeta-chain-associated protein kinase 70), a protein normally expressed near the surface membrane of T cells and natural killer cells. It is part of the T cell receptor, and plays a critical role in T-cell signaling. Native PTPN22 dephosphorylated ZAP70 at its activating tyrosine residue Tyr-493, but not at the regulatory tyrosine Tyr-319 [64]. ZAP70 is a member of TK group, Syk family in KinBase. Another member in Syk family is SYK (note: can it be PTPN22's substrates?).

• VAV, a proto-oncogene that is a member of the Dbl family of guanine nucleotide exchange factors (GEF) for the Rho family of GTP binding proteins. The protein is important in hematopoiesis, playing a role in T-cell and B-cell development and activation [64].

• CD3epsilon, together with CD3-gamma, -delta and -zeta, and the T-cell receptor alpha/beta and gamma/delta heterodimers, forms the T cell receptor-CD3 complex. This complex plays an important role in coupling antigen recognition to several intracellular signal-transduction pathways [64].

• T cell antigen receptor (TCR) zeta, a subunit of T cell receptor-CD3 complex. It plays an important role in coupling antigen recognition to several intracellular signal-transduction pathways [64].

• SKAP2 (Src kinase-associated phosphoprotein 2) [65]

• Valosin containing protein. a type II member of AAA+-ATPase family. It functions as a ubiquitin segregase that remodels multimeric protein complexes by extracting polyubiquitinated proteins for recycling or degradation by the proteasome [64].

• CSK forms a complex with PTPN22 and Lck via PTPN22's proline-rich sequence and CSK's SH3 domain [66, 67]. Both CSK and Lck are tyrosine phosphatase: CSK is tyrosine kinase group, CSK family; Lck is Src kinase group, Lck family in KinBase.

• Adaptor molecule Grb2 binds to PTPN22 via Grb2's N-terminal SH3 domain [45]. (SH3 bind to proline-rich sequence of PTPN22?)

• PKC regulates PTPN22/LYP by serine phosphorylation. PTPN22 is phosphorylated exclusively at Ser-35 by PKC both in vitro and in vivo. The status of Ser-35 phosphorylation may dictate the conformational state of the insert region and thus PTPN22 substrate recognition. Ser-35 phosphorylation impairs PTPN22 to inactivate the Src family kinases and down-regulate T cell receptor signaling [68].

• MAF or c-MAF, a transcription factor functions as a proto-oncogene. It regulates the phosphorylation at Tyr-21, Tyr-92, and Tyr-131 of c-MAF, in collaboration with kinase Tec [69]. While c-MAF is found from bony fish to primates, the kinase Tec and the phosphatase PTPN22 emerged much earlier and both of them are absent from ecdysozoa (internal database gOrtholog).

Here are some interesting papers have been incorporated into this page [70, 71, 72, 73, 74, 75, 76].

References

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Supplementary information

Below are the sequences used for position.

>hs_PTPN12 MEQVEILRKFIQRVQAMKSPDHNGEDNFARDFMRLRRLSTKYRTEKIYPTATGEKEENVKKNRYKDILPFDHSRVKLTLKTPSQDSDYINANFIKGVYGPKAYVATQGPLANTVIDFWRMIWEYNVVIIVMACREFEMGRKKCERYWPLYGEDPITFAPFKISCEDEQARTDYFIRTLLLEFQNESRRLYQFHYVNWPDHDVPSSFDSILDMISLMRKYQEHEDVPICIHCSAGCGRTGAICAIDYTWNLLKAGKIPEEFNVFNLIQEMRTQRHSAVQTKEQYELVHRAIAQLFEKQLQLYEIHGAQKIADGVNEINTENMVSSIEPEKQDSPPPKPPRTRSCLVEGDAKEEILQPPEPHPVPPILTPSPPSAFPTVTTVWQDNDRYHPKPVLHMVSSEQHSADLNRNYSKSTELPGKNESTIEQIDKKLERNLSFEIKKVPLQEGPKSFDGNTLLNRGHAIKIKSASPCIADKISKPQELSSDLNVGDTSQNSCVDCSVTQSNKVSVTPPEESQNSDTPPRPDRLPLDEKGHVTWSFHGPENAIPIPDLSEGNSSDINYQTRKTVSLTPSPTTQVETPDLVDHDNTSPLFRTPLSFTNPLHSDDSDSDERNSDGAVTQNKTNISTASATVSAATSTESISTRKVLPMSIARHNIAGTTHSGAEKDVDVSEDSPPPLPERTPESFVLASEHNTPVRSEWSELQSQERSEQKKSEGLITSENEKCDHPAGGIHYEMCIECPPTFSDKREQISENPTEATDIGFGNRCGKPKGPRDPPSEWT

>hs_PTPN22 MDQREILQKFLDEAQSKKITKEEFANEFLKLKRQSTKYKADKTYPTTVAEKPKNIKKNRYKDILPYDYSRVELSLITSDEDSSYINANFIKGVYGPKAYIATQGPLSTTLLDFWRMIWEYSVLIIVMACMEYEMGKKKCERYWAEPGEMQLEFGPFSVSCEAEKRKSDYIIRTLKVKFNSETRTIYQFHYKNWPDHDVPSSIDPILELIWDVRCYQEDDSVPICIHCSAGCGRTGVICAIDYTWMLLKDGIIPENFSVFSLIREMRTQRPSLVQTQEQYELVYNAVLELFKRQMDVIRDKHSGTESQAKHCIPEKNHTLQADSYSPNLPKSTTKAAKMMNQQRTKMEIKESSSFDFRTSEISAKEELVLHPAKSSTSFDFLELNYSFDKNADTTMKWQTKAFPIVGEPLQKHQSLDLGSLLFEGCSNSKPVNAAGRYFNSKVPITRTKSTPFELIQQRETKEVDSKENFSYLESQPHDSCFVEMQAQKVMHVSSAELNYSLPYDSKHQIRNASNVKHHDSSALGVYSYIPLVENPYFSSWPPSGTSSKMSLDLPEKQDGTVFPSSLLPTSSTSLFSYYNSHDSLSLNSPTNISSLLNQESAVLATAPRIDDEIPPPLPVRTPESFIVVEEAGEFSPNVPKSLSSAVKVKIGTSLEWGGTSEPKKFDDSVILRPSKSVKLRSPKSELHQDRSSPPPPLPERTLESFFLADEDCMQAQSIETYSTSYPDTMENSTSSKQTLKTPGKSFTRSKSLKILRNMKKSICNSCPPNKPAESVQSNNSSSFLNFGFANRFSKPKGPRNPPPTWNI