MAPK phosphatase

File:The inactivation of MAPKs by MKPs.jpgMAPK phosphatases are only found in eukaryotes and negatively regulate MAP kinases to act as negative feedback. MKPs are also known as dual-specificity phosphatases (DUSPs){{cite journal|last1=Comalada|first1=Mònica|last2=Lloberas|first2=Jorge|last3=Celada|first3=Antonio|title=MKP-1: A critical phosphatase in the biology of macrophages controlling the switch between proliferation and activation|journal=European Journal of Immunology|pages=1938–1948|language=en|doi=10.1002/eji.201242441|pmid=22865045|date=1 August 2012|volume=42|issue=8|doi-access=free}} because they deactivate MAPK by dephosphorylating the Threonine and the Tyrosine residues residing in MAPKs activation site.{{cite journal|last1=Kondoh|first1=Kunio|last2=Nishida|first2=Eisuke|title=Regulation of MAP kinases by MAP kinase phosphatases|journal=Biochimica et Biophysica Acta (BBA) - Molecular Cell Research|pages=1227–1237|doi=10.1016/j.bbamcr.2006.12.002|pmid=17208316|date=1 August 2007|volume=1773|issue=8|doi-access=free}} MKPs have a catalytic region at their C-terminus and a regulatory region at their N-terminus.{{cite journal|last1=Dickinson|first1=Robin J.|last2=Keyse|first2=Stephen M.|title=Diverse physiological functions for dual-specificity MAP kinase phosphatases|issue=22|journal=J Cell Sci|volume=119|pages=4607–4615|language=en|doi=10.1242/jcs.03266|pmid=17093265|date=15 November 2006|doi-access=free}} The position where the MAPK binds to MKP is found near the N-terminus of MKP. The binding is due to the electrostatic interactions of the positively charged residues on the MKP binding portion with the negatively charged residues on the MAPK binding site.{{cite journal|last1=Theodosiou|first1=Aspasia|last2=Ashworth|first2=Alan|title=MAP kinase phosphatases|journal=Genome Biology|date=1 January 2002|volume=3|issue=7|pages=reviews3009.1–reviews3009.10|issn=1465-6906|doi=10.1186/gb-2002-3-7-reviews3009|pmc=139386|pmid=12184814 |doi-access=free }}

There are 10{{cite journal|last1=Caunt|first1=Christopher J|last2=Keyse|first2=Stephen M|title=Dual-specificity MAP kinase phosphatases (MKPs)|journal=The FEBS Journal|date=7 November 2016|volume=280|issue=2|pages=489–504|doi=10.1111/j.1742-4658.2012.08716.x|issn=1742-464X|pmid=22812510|pmc=3594966}} main MKPs that can be further broken down into three sub-classes which are representative of either their genomic structure or the type of substrate (MAPK) they bind to.{{cite journal|last1=Theodosiou|first1=Aspasia|last2=Ashworth|first2=Alan|title=MAP kinase phosphatases|journal=Genome Biology|pages=reviews3009.1–reviews3009.10|date=1 January 2002|pmc=139386|pmid=12184814|volume=3|issue=7|doi=10.1186/gb-2002-3-7-reviews3009 |doi-access=free }} These include DUSP1, DUSP2, DUSP4 and DUSP5 that belong to subgroup 1. DUSP6, DUSP7, DUSP9 and DUSP10 belong to subgroup 2. DUSP8 and DUSP16 belong to subgroup 3, these subgroups are based on the genomic structure of the MKPs.{{cite journal|last1=Theodosiou|first1=Aspasia|last2=Ashworth|first2=Alan|title=MAP kinase phosphatases|journal=Genome Biology|pages=reviews3009.1–reviews3009.10|date=1 January 2002|pmc=139386|pmid=12184814|volume=3|issue=7|doi=10.1186/gb-2002-3-7-reviews3009 |doi-access=free }} The newest MKP-8 brings the total MKPs to 11, MKP-8 plays a role in inhibiting p38 kinase.{{cite journal|last1=Vasudevan|first1=Sanjeev A.|last2=Skoko|first2=John|last3=Wang|first3=Kuan|last4=Burlingame|first4=Susan M.|last5=Patel|first5=Parul N.|last6=Lazo|first6=John S.|last7=Nuchtern|first7=Jed G.|last8=Yang|first8=Jianhua|title=MKP-8, a novel MAPK phosphatase that inhibits p38 kinase|journal=Biochemical and Biophysical Research Communications|date=6 May 2005|volume=330|issue=2|pages=511–518|doi=10.1016/j.bbrc.2005.03.028|pmid=15796912}}

Dual specificity phosphatases (DUSPs) also belong to the family of protein thyrosine phosphatases.{{cite journal|last1=Jeffrey|first1=Kate L.|last2=Camps|first2=Montserrat|last3=Rommel|first3=Christian|last4=Mackay|first4=Charles R.|title=Targeting dual-specificity phosphatases: manipulating MAP kinase signalling and immune responses|journal=Nature Reviews Drug Discovery|date=May 2007|volume=6|issue=5|pages=391–403|doi=10.1038/nrd2289|pmid=17473844|s2cid=25916166 }} MKPs are grouped into type I, II and III; in which type I MKPs are located in the nuclear region, type II are located in the cytoplasmic region and type III are located in both the nuclear and cytoplasmic region.{{cite journal|last1=Kondoh|first1=Kunio|last2=Nishida|first2=Eisuke|title=Regulation of MAP kinases by MAP kinase phosphatases|journal=Biochimica et Biophysica Acta (BBA) - Molecular Cell Research|date=1 August 2007|volume=1773|issue=8|pages=1227–1237|doi=10.1016/j.bbamcr.2006.12.002|pmid=17208316|doi-access=free}} The different locations of these three types of MKPs allow for them to cause different types of signaling. For example, MKP-1 (a type I MKP) controls gene expression by inactivating the subcellular group of MAPKs.{{cite journal|last1=Wu|first1=J. J.|last2=Zhang|first2=L.|last3=Bennett|first3=A. M.|title=The Noncatalytic Amino Terminus of Mitogen-Activated Protein Kinase Phosphatase 1 Directs Nuclear Targeting and Serum Response Element Transcriptional Regulation|journal=Molecular and Cellular Biology|date=16 May 2005|volume=25|issue=11|pages=4792–4803|doi=10.1128/MCB.25.11.4792-4803.2005|pmid=15899879|pmc=1140620}}- Note that without the LXXLL motif (GFP-MKP-1_47-367) the MKP-1 cannot localize inside the nucleus and it comes before the CH2A domain.{{cite journal|last1=Wu|first1=J. J.|last2=Zhang|first2=L.|last3=Bennett|first3=A. M.|title=The Noncatalytic Amino Terminus of Mitogen-Activated Protein Kinase Phosphatase 1 Directs Nuclear Targeting and Serum Response Element Transcriptional Regulation|journal=Molecular and Cellular Biology|date=16 May 2005|volume=25|issue=11|pages=4792–4803|doi=10.1128/MCB.25.11.4792-4803.2005|pmid=15899879|pmc=1140620}} The newest MKP, MKP-8, belongs to group I because it is located in the nuclear region of the cell{{cite journal|last1=Vasudevan|first1=Sanjeev A.|last2=Skoko|first2=John|last3=Wang|first3=Kuan|last4=Burlingame|first4=Susan M.|last5=Patel|first5=Parul N.|last6=Lazo|first6=John S.|last7=Nuchtern|first7=Jed G.|last8=Yang|first8=Jianhua|title=MKP-8, a novel MAPK phosphatase that inhibits p38 kinase|journal=Biochemical and Biophysical Research Communications|date=6 May 2005|volume=330|issue=2|pages=511–518|doi=10.1016/j.bbrc.2005.03.028|pmid=15796912}} A recent study shows that histone deacetylase isoforms (HDAC1, -2, and -3) deacetylate MKP-1 and that this post-translational modification increases MAPK signaling and innate immune signaling.{{cite journal|doi=10.1189/jlb.1013565 | volume=95 | issue=4 | title=Histone deacetylase isoforms regulate innate immune responses by deacetylating mitogen-activated protein kinase phosphatase-1 | journal=J Leukoc Biol| pages=651–9 | pmid=24374966 | last1 = Jeong | first1 = Y | last2 = Du | first2 = R | last3 = Zhu | first3 = X| year=2014 | s2cid=40126163 }}

Although the N-terminal region is the quite distinct between each MKP, they all normally contain CH2 domains.{{cite journal|doi=10.1128/MCB.25.11.4792-4803.2005 | volume=25 | issue=11 | title=The Noncatalytic Amino Terminus of Mitogen-Activated Protein Kinase Phosphatase 1 Directs Nuclear Targeting and Serum Response Element Transcriptional Regulation | journal=Molecular and Cellular Biology | pages=4792–4803 | pmid=15899879 | pmc=1140620 | last1 = Wu | first1 = JJ | last2 = Zhang | first2 = L | last3 = Bennett | first3 = AM| year=2005 }} In MKP-1, MAPK binds to the active site that is between the CH2A and CHB domains located in the N-terminal.{{cite journal|last1=Wu|first1=J. J.|last2=Zhang|first2=L.|last3=Bennett|first3=A. M.|title=The Noncatalytic Amino Terminus of Mitogen-Activated Protein Kinase Phosphatase 1 Directs Nuclear Targeting and Serum Response Element Transcriptional Regulation|journal=Molecular and Cellular Biology|date=16 May 2005|volume=25|issue=11|pages=4792–4803|doi=10.1128/MCB.25.11.4792-4803.2005|pmid=15899879|pmc=1140620}}{{cite journal|last1=BARDWELL|first1=A. Jane|last2=ABDOLLAHI|first2=Mahsa|last3=BARDWELL|first3=Lee|title=Docking sites on mitogen-activated protein kinase (MAPK) kinases, MAPK phosphatases and the Elk-1 transcription factor compete for MAPK binding and are crucial for enzymic activity|journal=Biochemical Journal|date=15 March 2003|volume=370|issue=3|pages=1077–1085|doi=10.1042/BJ20021806|pmid=12529172|pmc=1223246}}

An example of a type II MKP is MKP-3 which, regulates the activity of ERK2 by deposphorylating it and holding it in the cytoplasmic region.{{cite journal|last1=Karlsson|first1=Maria|last2=Mathers|first2=Joanne|last3=Dickinson|first3=Robin J.|last4=Mandl|first4=Margret|last5=Keyse|first5=Stephen M.|title=Both Nuclear-Cytoplasmic Shuttling of the Dual Specificity Phosphatase MKP-3 and Its Ability to Anchor MAP Kinase in the Cytoplasm Are Mediated by a Conserved Nuclear Export Signal|journal=Journal of Biological Chemistry|date=1 October 2004|volume=279|issue=40|pages=41882–41891|doi=10.1074/jbc.M406720200|language=en|issn=0021-9258|pmid=15269220|doi-access=free}} MKP-3 also binds to ERK2 regardless of whether it is phosphorylated or not.{{cite journal|last1=Camps|first1=M.|title=Catalytic Activation of the Phosphatase MKP-3 by ERK2 Mitogen-Activated Protein Kinase|journal=Science|date=22 May 1998|volume=280|issue=5367|pages=1262–1265|doi=10.1126/science.280.5367.1262|pmid=9596579|bibcode=1998Sci...280.1262C |doi-access=free}} MKP-4 is another MKP that belongs to Type I and, is distinct from other MKPs in this subgroup because it is only found in placenta, kidney and embryonic liver cells.{{cite journal|last1=Muda|first1=M.|last2=Boschert|first2=U.|last3=Smith|first3=A.|last4=Antonsson|first4=B.|last5=Gillieron|first5=C.|last6=Chabert|first6=C.|last7=Camps|first7=M.|last8=Martinou|first8=I.|last9=Ashworth|first9=A.|last10=Arkinstall|first10=S.|title=Molecular Cloning and Functional Characterization of a Novel Mitogen-activated Protein Kinase Phosphatase, MKP-4|journal=Journal of Biological Chemistry|date=21 February 1997|volume=272|issue=8|pages=5141–5151|doi=10.1074/jbc.272.8.5141|pmid=9030581|doi-access=free}} MKP-5 is a type III MKP that binds specifically to p38 and SPK/JNK and is found both in the cytoplasmic and nuclear regions of a cell.{{cite journal|last1=Tanoue|first1=T.|title=Molecular Cloning and Characterization of a Novel Dual Specificity Phosphatase, MKP-5|journal=Journal of Biological Chemistry|date=9 July 1999|volume=274|issue=28|pages=19949–19956|doi=10.1074/jbc.274.28.19949|pmid=10391943|doi-access=free}} MKP-5 is only located in the heart, lung, liver, kidney and skeletal muscle cells.{{cite journal|last1=Kondoh|first1=Kunio|last2=Nishida|first2=Eisuke|title=Regulation of MAP kinases by MAP kinase phosphatases|journal=Biochimica et Biophysica Acta (BBA) - Molecular Cell Research|date=1 August 2007|volume=1773|issue=8|pages=1227–1237|doi=10.1016/j.bbamcr.2006.12.002|pmid=17208316|doi-access=free}}

There are also MKPs that belong to a group called Atypical MKPs. For example, Vaccina H1-related (VHR) is an atypical MKP because it only has the DUSP region.{{cite journal|last1=Kondoh|first1=Kunio|last2=Nishida|first2=Eisuke|title=Regulation of MAP kinases by MAP kinase phosphatases|journal=Biochimica et Biophysica Acta (BBA) - Molecular Cell Research|date=1 August 2007|volume=1773|issue=8|pages=1227–1237|doi=10.1016/j.bbamcr.2006.12.002|pmid=17208316|doi-access=free}} VHR is only found in lymphoid and hematopoietic cells, and it inactivates the ERK1/2 and JNKs in T-cell receptors.{{cite journal|last1=Alonso|first1=A.|last2=Saxena|first2=M.|last3=Williams|first3=S.|last4=Mustelin|first4=T.|title=Inhibitory Role for Dual Specificity Phosphatase VHR in T Cell Antigen Receptor and CD28-induced Erk and Jnk Activation|journal=Journal of Biological Chemistry|date=20 November 2000|volume=276|issue=7|pages=4766–4771|doi=10.1074/jbc.M006497200|pmid=11085983|doi-access=free}} VHR also induces cell cycle arrest.{{cite journal|last1=Rahmouni|first1=Souad|last2=Cerignoli|first2=Fabio|last3=Alonso|first3=Andres|last4=Tsutji|first4=Toshiya|last5=Henkens|first5=Rachel|last6=Zhu|first6=Changjun|last7=Louis-dit-Sully|first7=Christine|last8=Moutschen|first8=Michel|last9=Jiang|first9=Wei|last10=Mustelin|first10=Tomas|title=Loss of the VHR dual-specific phosphatase causescell-cycle arrest and senescence|journal=Nature Cell Biology|date=9 April 2006|volume=8|issue=5|pages=524–531|doi=10.1038/ncb1398|pmid=16604064|s2cid=20976640 }}{{cite journal|last1=Rahmouni|first1=Souad|last2=Cerignoli|first2=Fabio|last3=Alonso|first3=Andres|last4=Tsutji|first4=Toshiya|last5=Henkens|first5=Rachel|last6=Zhu|first6=Changjun|last7=Louis-dit-Sully|first7=Christine|last8=Moutschen|first8=Michel|last9=Jiang|first9=Wei|last10=Mustelin|first10=Tomas|title=Loss of the VHR dual-specific phosphatase causes cell-cycle arrest and senescence|journal=Nature Cell Biology|date=1 May 2006|volume=8|issue=5|pages=524–531|doi=10.1038/ncb1398|issn=1465-7392|pmid=16604064|s2cid=20976640 }}

{{reflist}}

{{Protein tyrosine phosphatases}}

{{Intracellular signaling peptides and proteins}}

{{MAP kinase activation}}

Category:Cell signaling

Category:Enzymes

Category:Protein kinases