Phosphatase Subfamily PTPN12

Phosphatase Classification: Fold CC1:Superfamily CC1: Family PTP: Subfamily PTPN12 (PTP-PEST)

Domain

Phosphatase domain has crystal structure solved [1].

The noncatalytic domain of PTPN22/LYP contains four proline-rich potential SH3 domain binding sites and an NXXY motif that, if phosphorylated, may be recognized by phosphotyrosine binding (PTB) domains [2].

The region of 301-320 in PTPN22 interactions with its phosphatase domain and reduces its catalytic activity [3].

Functions

PTPN12 (PTP-PEST/PTPG1)

PTPN12 is widely expressed in different tissues and at relatively low level in brain (GTEx).

PTPN18 (BDP1/PTP-HSCF)

PTPN18 is most abundantly expressed in spleen (GTEx).

PTPN22 (LYP/PEP/PTPN8)

PTPN22 predominantly in hematopoietic tissues

PTPN22 mainly functions in immune system, particularly its R620W variant 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 [4], in consistent with earlier study [2].

PTPN22 is expressed in macrophages and plays a critical role in regulating macrophage activation and polarization [5].

R620W variant associated with multiple autoimmune diseases

Missense single-nucleotide polymorphism (SNP) R620W is associated with different autoimmune diseases [6, 7, 8, 9], including rheumatoid arthritis (RA) [10, 11, 12, 13], systemic lupus erythematosus (SLE) [12, 14, 15], type 1 diabetes (T1D) [6], Hashimoto thyroiditis [6], juvenile idiopathic arthritis (JIA) [16], Grave's disease (GD) [16]. However, multiple sclerosis (MS) did not show association with R620W [6].

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 [17, 18]. 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 [19]. 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 [19].

Substrates

• 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 [20]. On the other hand, Lck phosphorylates PTPN22 at Tyr-536, playing an inhibitory role on the phosphatase activity [19]. 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 [20]. 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 [20].

• 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 [20].

• 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 [20].

• (Src kinase-associated phosphoprotein 2) [21]

• 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 [20].

Interacting partners

PTPN22 interacts with tyrosine kinase CSK via PTPN22's proline-rich sequence and CSK's SH3 domain [22, 23].

PTPN22 interacts with adaptor molecule Grb2 at Grb2's N-terminal SH3 domain [4]. (SH3 bind to proline-rich sequence of PTPN22?)

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 [24].

References

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Supplementary information

Below are the sequences used for position.

>PTPN22 MDQREILQKFLDEAQSKKITKEEFANEFLKLKRQSTKYKADKTYPTTVAEKPKNIKKNRYKDILPYDYSRVELSLITSDEDSSYINANFIKGVYGPKAYIATQGPLSTTLLDFWRMIWEYSVLIIVMACMEYEMGKKKCERYWAEPGEMQLEFGPFSVSCEAEKRKSDYIIRTLKVKFNSETRTIYQFHYKNWPDHDVPSSIDPILELIWDVRCYQEDDSVPICIHCSAGCGRTGVICAIDYTWMLLKDGIIPENFSVFSLIREMRTQRPSLVQTQEQYELVYNAVLELFKRQMDVIRDKHSGTESQAKHCIPEKNHTLQADSYSPNLPKSTTKAAKMMNQQRTKMEIKESSSFDFRTSEISAKEELVLHPAKSSTSFDFLELNYSFDKNADTTMKWQTKAFPIVGEPLQKHQSLDLGSLLFEGCSNSKPVNAAGRYFNSKVPITRTKSTPFELIQQRETKEVDSKENFSYLESQPHDSCFVEMQAQKVMHVSSAELNYSLPYDSKHQIRNASNVKHHDSSALGVYSYIPLVENPYFSSWPPSGTSSKMSLDLPEKQDGTVFPSSLLPTSSTSLFSYYNSHDSLSLNSPTNISSLLNQESAVLATAPRIDDEIPPPLPVRTPESFIVVEEAGEFSPNVPKSLSSAVKVKIGTSLEWGGTSEPKKFDDSVILRPSKSVKLRSPKSELHQDRSSPPPPLPERTLESFFLADEDCMQAQSIETYSTSYPDTMENSTSSKQTLKTPGKSFTRSKSLKILRNMKKSICNSCPPNKPAESVQSNNSSSFLNFGFANRFSKPKGPRNPPPTWNI