Difference between revisions of "Phosphatase Subfamily PTPN12"
(→PTPN22 (LYP/PEP/PTPN8)) |
|||
| Line 60: | Line 60: | ||
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 <cite>Fiorillo10</cite>. 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 <cite>Fiorillo10</cite>. | 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 <cite>Fiorillo10</cite>. 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 <cite>Fiorillo10</cite>. | ||
| − | ====== Substrates ====== | + | ====== Substrates and interacting partners ====== |
* [http://en.wikipedia.org/wiki/Lck '''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 <cite>Wu06</cite>. On the other hand, Lck phosphorylates PTPN22 at Tyr-536, playing an inhibitory role on the phosphatase activity <cite>Fiorillo10</cite>. 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?). | * [http://en.wikipedia.org/wiki/Lck '''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 <cite>Wu06</cite>. On the other hand, Lck phosphorylates PTPN22 at Tyr-536, playing an inhibitory role on the phosphatase activity <cite>Fiorillo10</cite>. 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?). | ||
| Line 75: | Line 75: | ||
* [http://en.wikipedia.org/wiki/Valosin-containing_protein '''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 <cite>Wu06</cite>. | * [http://en.wikipedia.org/wiki/Valosin-containing_protein '''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 <cite>Wu06</cite>. | ||
| − | + | * '''CSK''' forms a complex with PTPN22 and Lck via PTPN22's proline-rich sequence and CSK's SH3 domain <cite>Gregorieff98, delaPuerta13</cite>. Both CSK and Lck are tyrosine phosphatase: CSK is tyrosine kinase group, CSK family; Lck is Src kinase group, Lck family in KinBase. | |
| − | '''CSK''' forms a complex with PTPN22 and Lck via PTPN22's proline-rich sequence and CSK's SH3 domain <cite>Gregorieff98, delaPuerta13</cite>. Both CSK and Lck are tyrosine phosphatase: CSK is tyrosine kinase group, CSK family; Lck is Src kinase group, Lck family in KinBase. | + | |
| − | [http://en.wikipedia.org/wiki/GRB2 | + | * [http://en.wikipedia.org/wiki/GRB2 Adaptor molecule '''Grb2'''] binds to PTPN22 via Grb2's N-terminal SH3 domain <cite>Hill02</cite>. (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 <cite>Yu07</cite>. | + | * '''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 <cite>Yu07</cite>. |
Here are some interesting papers have been incorporated into this page <cite>Burn11, Menard11, Chien03, Chang12, Negro12, Vang13, Wu14 | Here are some interesting papers have been incorporated into this page <cite>Burn11, Menard11, Chien03, Chang12, Negro12, Vang13, Wu14 | ||
Revision as of 17:17, 13 March 2015
Phosphatase Classification: Fold CC1:Superfamily CC1: Family PTP: Subfamily PTPN12 (PTP-PEST)
Evolution
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 according to GTEx. The expression pattern is consistent with earlier studies [4, 5, 6].
PTPN12 have below substrates and/or interacting partners:
- p130Cas/BCAR1 [7]. p130Cas/BCAR1 is an adaptor protein that regulates multiple signaling pathways leading to cell adhesion, migration, invasion, apoptosis, hypoxia and mechanical forces. p130Cas/BCAR1 plays a role in cell transformation and cancer progression and alterations of p130Cas/BCAR1 expression and the resulting activation of selective signalling are determinants for the occurrence of different types of human tumors.
- PSTPIP1 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 [8, 9, 10, 11].
- 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 [12].
- Insulin receptor (IR). IR plays a key role in the regulation of glucose homeostasis, a functional process that under degenerate conditions may result in a range of clinical manifestations including diabetes and cancer. It is a tyrosine phosphatase of InsR family in KinBase [13].
- CSK?
- 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/PTP-PEST 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 [14]. 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 PTP-PEST [15]. (note: synergy between PTB and CH2 domain?) The interaction is stimulated by activators of protein kinase C (PKC) [14].
- Cyclic AMP-dependent protein kinase (PKA) and protein kinase C (PKC) regulates PTPN12/PTP-PEST 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 [16].
PPTN12/PTP-PEST is implicated in cancer [17].
PTPN18 (BDP1/PTP-HSCF)
PTPN18 was first identified as Brain Derived Phosphatase (BDP1) [18]. 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 blodd, 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 [8, 9, 10].
- 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 [12].
- CSK. Like PTPN12 and PTPN22, PTPN18 interacts with CSK, too. However, the interaction is not mediated by CSK SH3 domain, instead by CSK SH2 domain [19].
- HER2/ErbB2? PTPN18 is a negative regulator of HER2/ErbB2 [20]. But it is unclear whether it dephosphorylates HER2/ErbB2, directly.
PTPN22 (LYP/PEP/PTPN8)
PTPN22 predominantly in hematopoietic tissues
PTPN22 (aka lymphoid tyrosine phosphatase, LYP) 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 [21], in consistent with earlier study [2].
PTPN22 is expressed in macrophages and plays a critical role in regulating macrophage activation and polarization [22].
R620W variant associated with multiple autoimmune diseases
Missense single-nucleotide polymorphism (SNP) R620W is associated with different autoimmune diseases [23, 24, 25, 26], including rheumatoid arthritis (RA) [27, 28, 29, 30], systemic lupus erythematosus (SLE) [29, 31, 32], type 1 diabetes (T1D) [23], Hashimoto thyroiditis [23], juvenile idiopathic arthritis (JIA) [33], Grave's disease (GD) [33]. However, multiple sclerosis (MS) did not show association with R620W [23].
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 [34, 35]. 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 [36]. 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 [36].
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 [37]. On the other hand, Lck phosphorylates PTPN22 at Tyr-536, playing an inhibitory role on the phosphatase activity [36]. 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 [37]. 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 [37].
- 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 [37].
- 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 [37].
- 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 [37].
- CSK forms a complex with PTPN22 and Lck via PTPN22's proline-rich sequence and CSK's SH3 domain [39, 40]. 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 [21]. (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 [41].
Here are some interesting papers have been incorporated into this page [42, 43, 44, 45, 46, 47, 48].
References
Error fetching PMID 15208781:
Error fetching PMID 16697661:
Error fetching PMID 21515266:
Error fetching PMID 22427951:
Error fetching PMID 23913970:
Error fetching PMID 8626541:
Error fetching PMID 12764153:
Error fetching PMID 10068674:
Error fetching PMID 11163214:
Error fetching PMID 15719322:
Error fetching PMID 23359562:
Error fetching PMID 9422760:
Error fetching PMID 20538612:
Error fetching PMID 7520867:
Error fetching PMID 8887669:
Error fetching PMID 14660651:
Error fetching PMID 9582365:
Error fetching PMID 7929214:
Error fetching PMID 11882361:
Error fetching PMID 8950995:
Error fetching PMID 15273934:
Error fetching PMID 16760194:
Error fetching PMID 19586056:
Error fetching PMID 21804190:
Error fetching PMID 17237219:
Error fetching PMID 22569400:
Error fetching PMID 15641066:
Error fetching PMID 16380915:
Error fetching PMID 16273109:
Error fetching PMID 17729039:
Error fetching PMID 23333624:
Error fetching PMID 15504986:
Error fetching PMID 9265651:
Error fetching PMID 25003765:
Error fetching PMID 1472029:
Error fetching PMID 7509295:
Error fetching PMID 19371084:
Error fetching PMID 11158295:
Error fetching PMID 11971877:
Error fetching PMID 9804817:
Error fetching PMID 16461343:
Error fetching PMID 24498279:
Error fetching PMID 8454633:
Error fetching PMID 1932742:
Error fetching PMID 18056643:
Error fetching PMID 21719704:
- Error fetching PMID 19371084:
- Error fetching PMID 10068674:
- Error fetching PMID 19586056:
- Error fetching PMID 1932742:
- Error fetching PMID 1472029:
- Error fetching PMID 8454633:
- Error fetching PMID 8887669:
- Error fetching PMID 9265651:
- Error fetching PMID 9422760:
- Error fetching PMID 9804817:
- Error fetching PMID 11971877:
- Error fetching PMID 11163214:
- Error fetching PMID 7929214:
- Error fetching PMID 8626541:
- Error fetching PMID 7520867:
- Error fetching PMID 7509295:
- Error fetching PMID 8950995:
- Error fetching PMID 11158295:
- Error fetching PMID 14660651:
- Error fetching PMID 11882361:
- Error fetching PMID 23913970:
- Error fetching PMID 15719322:
- Error fetching PMID 16697661:
- Error fetching PMID 17729039:
- Error fetching PMID 25003765:
- Error fetching PMID 15208781:
- Error fetching PMID 16380915:
- Error fetching PMID 15641066:
- Error fetching PMID 17237219:
- Error fetching PMID 15273934:
- Error fetching PMID 15504986:
- Error fetching PMID 16760194:
- Error fetching PMID 16273109:
- Error fetching PMID 18299186:
- Error fetching PMID 20538612:
- Error fetching PMID 16461343:
- Error fetching PMID 21719704:
- Error fetching PMID 9582365:
- Error fetching PMID 23359562:
- Error fetching PMID 18056643:
- Error fetching PMID 21515266:
- Error fetching PMID 21804190:
- Error fetching PMID 12764153:
- Error fetching PMID 22427951:
- Error fetching PMID 22569400:
- Error fetching PMID 23333624:
- Error fetching PMID 24498279:
Supplementary information
Below are the sequences used for position.
>hs_PTPN12 MEQVEILRKFIQRVQAMKSPDHNGEDNFARDFMRLRRLSTKYRTEKIYPTATGEKEENVKKNRYKDILPFDHSRVKLTLKTPSQDSDYINANFIKGVYGPKAYVATQGPLANTVIDFWRMIWEYNVVIIVMACREFEMGRKKCERYWPLYGEDPITFAPFKISCEDEQARTDYFIRTLLLEFQNESRRLYQFHYVNWPDHDVPSSFDSILDMISLMRKYQEHEDVPICIHCSAGCGRTGAICAIDYTWNLLKAGKIPEEFNVFNLIQEMRTQRHSAVQTKEQYELVHRAIAQLFEKQLQLYEIHGAQKIADGVNEINTENMVSSIEPEKQDSPPPKPPRTRSCLVEGDAKEEILQPPEPHPVPPILTPSPPSAFPTVTTVWQDNDRYHPKPVLHMVSSEQHSADLNRNYSKSTELPGKNESTIEQIDKKLERNLSFEIKKVPLQEGPKSFDGNTLLNRGHAIKIKSASPCIADKISKPQELSSDLNVGDTSQNSCVDCSVTQSNKVSVTPPEESQNSDTPPRPDRLPLDEKGHVTWSFHGPENAIPIPDLSEGNSSDINYQTRKTVSLTPSPTTQVETPDLVDHDNTSPLFRTPLSFTNPLHSDDSDSDERNSDGAVTQNKTNISTASATVSAATSTESISTRKVLPMSIARHNIAGTTHSGAEKDVDVSEDSPPPLPERTPESFVLASEHNTPVRSEWSELQSQERSEQKKSEGLITSENEKCDHPAGGIHYEMCIECPPTFSDKREQISENPTEATDIGFGNRCGKPKGPRDPPSEWT
>hs_PTPN22
MDQREILQKFLDEAQSKKITKEEFANEFLKLKRQSTKYKADKTYPTTVAEKPKNIKKNRYKDILPYDYSRVELSLITSDEDSSYINANFIKGVYGPKAYIATQGPLSTTLLDFWRMIWEYSVLIIVMACMEYEMGKKKCERYWAEPGEMQLEFGPFSVSCEAEKRKSDYIIRTLKVKFNSETRTIYQFHYKNWPDHDVPSSIDPILELIWDVRCYQEDDSVPICIHCSAGCGRTGVICAIDYTWMLLKDGIIPENFSVFSLIREMRTQRPSLVQTQEQYELVYNAVLELFKRQMDVIRDKHSGTESQAKHCIPEKNHTLQADSYSPNLPKSTTKAAKMMNQQRTKMEIKESSSFDFRTSEISAKEELVLHPAKSSTSFDFLELNYSFDKNADTTMKWQTKAFPIVGEPLQKHQSLDLGSLLFEGCSNSKPVNAAGRYFNSKVPITRTKSTPFELIQQRETKEVDSKENFSYLESQPHDSCFVEMQAQKVMHVSSAELNYSLPYDSKHQIRNASNVKHHDSSALGVYSYIPLVENPYFSSWPPSGTSSKMSLDLPEKQDGTVFPSSLLPTSSTSLFSYYNSHDSLSLNSPTNISSLLNQESAVLATAPRIDDEIPPPLPVRTPESFIVVEEAGEFSPNVPKSLSSAVKVKIGTSLEWGGTSEPKKFDDSVILRPSKSVKLRSPKSELHQDRSSPPPPLPERTLESFFLADEDCMQAQSIETYSTSYPDTMENSTSSKQTLKTPGKSFTRSKSLKILRNMKKSICNSCPPNKPAESVQSNNSSSFLNFGFANRFSKPKGPRNPPPTWNI
