Phosphatase Subfamily PTPN12 - Revision history

Gerard at 03:16, 16 May 2016

2016-05-16T03:16:37Z

Gerard: /* PTPN22 predominantly in hematopoietic tissues */

2016-05-16T03:14:50Z

‎PTPN22 predominantly in hematopoietic tissues

Gerard: /* PTPN22 predominantly in hematopoietic tissues */

2016-05-16T03:14:00Z

‎PTPN22 predominantly in hematopoietic tissues

Gerard: /* PTPN18 (BDP1/PTP-HSCF) */

2016-05-16T03:11:41Z

‎PTPN18 (BDP1/PTP-HSCF)

Gerard: /* PTPN12 (PTP-PEST/PTPG1) */

2016-05-16T03:09:58Z

‎PTPN12 (PTP-PEST/PTPG1)

Gerard: /* PTPN12 (PTP-PEST/PTPG1) */

2016-05-16T03:09:25Z

‎PTPN12 (PTP-PEST/PTPG1)

Gerard: /* Functions */

2016-05-16T03:03:36Z

‎Functions

Gerard at 01:18, 9 March 2016

2016-03-09T01:18:32Z

Gerard at 01:15, 9 March 2016

2016-03-09T01:15:05Z

Mark: /* References */

2015-06-17T18:40:15Z

‎References

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 __NOTOC__
 [[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_CC1|Fold CC1]]:[[Phosphatase_Superfamily_CC1|Superfamily CC1]]: [[Phosphatase_Family_PTP|Family PTP]]: [[Phosphatase_Subfamily_PTPN12|Subfamily PTPN12]]
 ===Evolution===
-PTPN12 subfamily emerged in holozoa and duplicated in vertebrates, but is lost in ecdysozoa.
+PTPN12 emerged in holozoa and is duplicated in vertebrates, but is lost in ecdysozoa.
-===Domain ===
+===Domain Architecture ===
-PTPN12 subfamily has a N-terminal phosphatase domain (crystal structure see <cite>Tsai09</cite>) and a C-terminal region containing several proline-rich sequences, which mediate their interactions with SH3-domain-containing proteins. Also, the region of 301-320 in PTPN22 interactions with its phosphatase domain and reduces its catalytic activity <cite>Liu09</cite>.
+PTPN12 subfamily has a N-terminal phosphatase domain (crystal structure see <cite>Tsai09</cite>) 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 <cite>Liu09</cite>.
 ===Functions===

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 ===== PTPN22 (LYP/PEP/PTPN8) =====
-====== PTPN22 predominantly in hematopoietic tissues ======
+====== 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 ([http://www.gtexportal.org/home/gene/PTPN22 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 <cite>Hill02, Cohen99</cite>.
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 * In T cells, PTPN22 negatively regulates T cell receptor (TCR) signaling <cite> Ivashkiv13</cite>.
 * 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 <cite> Ivashkiv13</cite>.
-* PTPN22 is expressed in macrophages and plays a critical role in regulating [http://ac.els-cdn.com/S1074761314002283/1-s2.0-S1074761314002283-main.pdf?_tid=875f236c-c8df-11e4-8db9-00000aab0f27&acdnat=1426182490_66a74cd519b27c92230b82b174ccbb46 macrophage activation and polarization] <cite>Chang13</cite>.
+* PTPN22 is expressed in macrophages and plays a critical role in regulating macrophage activation and polarization <cite>Chang13</cite>.
 ====== R620W variant associated with multiple autoimmune diseases ======

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 ===== PTPN22 (LYP/PEP/PTPN8) =====
 ====== PTPN22 predominantly in hematopoietic tissues ======
-Human 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 ([http://www.gtexportal.org/home/gene/PTPN22 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 <cite>Hill02</cite>, in consistent with earlier study <cite>Cohen99</cite>.
+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 ([http://www.gtexportal.org/home/gene/PTPN22 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 <cite>Hill02, Cohen99</cite>.
-Human PTPN22 (LYP) functions in different ways in different blood cells. For instance,
+Human PTPN22 has several described functions:
-* In T lineage cells, PTPN22 negatively regulates T cell receptor (TCR) signaling <cite> Ivashkiv13</cite>.
+* In T cells, PTPN22 negatively regulates T cell receptor (TCR) signaling <cite> Ivashkiv13</cite>.
-* In myeloid lineage 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 <cite> Ivashkiv13</cite>.
+* 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 <cite> Ivashkiv13</cite>.
 * PTPN22 is expressed in macrophages and plays a critical role in regulating [http://ac.els-cdn.com/S1074761314002283/1-s2.0-S1074761314002283-main.pdf?_tid=875f236c-c8df-11e4-8db9-00000aab0f27&acdnat=1426182490_66a74cd519b27c92230b82b174ccbb46 macrophage activation and polarization] <cite>Chang13</cite>.

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 * [http://en.wikipedia.org/wiki/ABL_%28gene%29 '''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 <cite>Cong00</cite>.
-* '''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 <cite>Wang01</cite>.
+* '''CSK'''. Like PTPN12 and PTPN22, PTPN18 interacts with CSK. However, the interaction is not mediated by CSK SH3 domain, instead by CSK SH2 domain <cite>Wang01</cite>.
-* '''HER2/ErbB2?''' PTPN18 is a negative regulator of HER2/ErbB2 <cite>Gensler04</cite>. But it is unclear whether it dephosphorylates HER2/ErbB2, directly.
+* '''HER2/ErbB2''' PTPN18 is a negative regulator of HER2/ErbB2 <cite>Gensler04</cite> but it is unclear whether it ErbB2 is a direct substrate.
 ===== PTPN22 (LYP/PEP/PTPN8) =====

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 * 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 <cite>Garton94</cite>.
-* [Phosphatase_Subfamily_PPP1C|'''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 <cite>Nakamura10</cite>.
+* [[Phosphatase_Subfamily_PPP1C|'''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 <cite>Nakamura10</cite>.
 * '''ERK1/2''' phosphorylate PTPN12 at Serine-571 <cite>Zheng11</cite>.

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 PTPN12 has the following substrates and/or interacting partners involved in lymphocyte activation, cytoskeleton organization etc.
-* [http://en.wikipedia.org/wiki/BCAR1 '''p130Cas/BCAR1'''] <cite>Garton96</cite>. p130Cas/BCAR1 is an adaptor protein that regulates multiple signaling pathways and implicated in cancers. PTPN12/PTP-PEST 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 <cite>Garton97, Garton99</cite>. PTPN12 also interacts with other members of the p130(Cas) family ('''Hef1''' and '''Sin''') via their SH3 domain in vitro <cite>Cote98</cite>.
+* [http://en.wikipedia.org/wiki/BCAR1 '''p130Cas/BCAR1'''] <cite>Garton96</cite>. 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 <cite>Garton97, Garton99</cite>. PTPN12 also interacts with other members of the p130(Cas) family ('''Hef1''' and '''Sin''') via their SH3 domain in vitro <cite>Cote98</cite>.
 * [http://en.wikipedia.org/wiki/PSTPIP1 '''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 <cite>Spencer97, Dowbenko98, Wu98, Li98, Wise02</cite>. PTPN12 dephosphorylates Tyr-344 of PSTPIP1 and prevents its interaction with SH2 domain-containing proteins <cite>Cote02</cite>.
-* [http://en.wikipedia.org/wiki/Wiskott%E2%80%93Aldrich_syndrome_protein '''WASP''']. WASP is involved in the transduction of signals from receptors on the cell surface to the actin cytoskeleton. PTPN12/PTP-PEST can dephosphorylate WASP on Tyr-291. PTPN12 does not interact with WASP, directly; Instead, PTPN12 interacts with PSTPIP, which form a complex with WASP <cite>Cote02</cite>.
+* [http://en.wikipedia.org/wiki/Wiskott%E2%80%93Aldrich_syndrome_protein '''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 <cite>Cote02</cite>.
 * [http://en.wikipedia.org/wiki/ABL_%28gene%29 '''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 <cite>Cong00</cite>.
-* [http://en.wikipedia.org/wiki/PTK2B '''PYK2/PTK2B/CADTK/RAFTK/CAKbeta''']. PTPN12/PTP-PEST dephosphorylates PYK2 at its major autophosphorylation site Tyr-402 and activation loop tyrosine residues, Tyr-579 and Tyr-580. PYK2 is a member of tyrosine kinase group, FAK family in KinBase. However, another kinase of the same family, FAK is a poor PTP-PEST substrate <cite>Lyons01</cite>.  Both PYK2 and FAK colocalize with, bind to, and induce tyrosine phosphorylation of p130Cas and paxillin. Interestingly, p130Cas and paxilin are the substrates of PTPN12/PTP-PEST (see below).
+* [http://en.wikipedia.org/wiki/PTK2B '''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 <cite>Lyons01</cite>.  Both PYK2 and FAK colocalize with, bind to, and induce tyrosine phosphorylation of p130Cas and paxillin, which are also substrates of PTPN12.
-* [http://en.wikipedia.org/wiki/Insulin_receptor '''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 <cite>Yang02</cite>.
+* [http://en.wikipedia.org/wiki/Insulin_receptor '''Insulin receptor''' (InsR)]. InsR is a receptor tyrosine kinase that plays a key role in the regulation of glucose homeostasis  <cite>Yang02</cite>.
-* [http://en.wikipedia.org/wiki/CTNND1 CTNND1/p120Cas], a gene functions in adhesion between cells and signal transduction. PTPN12/PTP-PEST dephosphorylates p120Cas at tyrosine 335 in the N-terminal domain <cite>Espejo14</cite>.
+* [http://en.wikipedia.org/wiki/CTNND1 CTNND1/p120Cas], a gene functions in adhesion between cells and signal transduction. PTPN12 dephosphorylates p120Cas at Y335 in the N-terminal domain <cite>Espejo14</cite>.
-* [http://en.wikipedia.org/wiki/Paxillin '''Paxilin'''], an adaptor protein is a substrate and interacting partner of PTPN12/PTP-PEST  <cite>Shen98, Shen00</cite>. It has a N-terminal paxilin domain and C-terminal four tandem LIM domains. The interaction is mediated by proline-rich region of PTPN12 and LIM3 and LIM4 of paxilin <cite>Cote99</cite>.
+* [http://en.wikipedia.org/wiki/Paxillin '''Paxilin'''], an adaptor protein is a substrate and interacting partner of PTPN12 <cite>Shen98, Shen00</cite>. 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 <cite>Cote99</cite>.
-* [http://en.wikipedia.org/wiki/TGFB1I1 '''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/PTP-PEST binds to HIC-5 via its proline-rich sequence the 3rd LIM domain (LIM3) of HIC-5 <cite>Nishiya99</cite>.
+* [http://en.wikipedia.org/wiki/TGFB1I1 '''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 <cite>Nishiya99</cite>.
 * STAT3? PTPN12 was associated with STAT3 and induced STAT3 dephosphorylation. However, it is unclear whether it is by direct phosphorylation <cite>Su13</cite>.
-* [http://en.wikipedia.org/wiki/SHC1 '''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 ([http://atlasgeneticsoncology.org/Genes/Images/SHC1Fig3.png domain combination picture] and [http://atlasgeneticsoncology.org/Genes/SHC1ID42287ch1q21.html 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 <cite>Habib94</cite>.  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 <cite>Charest94</cite>. (note: synergy between PTB and CH2 domain?) The interaction is stimulated by activators of protein kinase C (PKC) <cite>Habib94</cite>.
+* [http://en.wikipedia.org/wiki/SHC1 '''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 ([http://atlasgeneticsoncology.org/Genes/Images/SHC1Fig3.png domain combination picture] and [http://atlasgeneticsoncology.org/Genes/SHC1ID42287ch1q21.html 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 <cite>Habib94</cite>.  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 <cite>Charest94</cite>. (note: synergy between PTB and CH2 domain?) The interaction is stimulated by activators of protein kinase C (PKC) <cite>Habib94</cite>.
-* 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 <cite>Garton94</cite>.
+* 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 <cite>Garton94</cite>.
-* [Phosphatase_Subfamily_PPP1C|'''PPP1CA/PP1'''] catalytic subunit, alpha isozyme]. PPP1C associates with PTPN12/PTP-PEST C-terminal region (proline-rich sequence?) and dephosphorylates PTPN12/PTP-PEST at pSer-9, which is phosphorylated by PKA <cite>Nakamura10</cite>.
+* [Phosphatase_Subfamily_PPP1C|'''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 <cite>Nakamura10</cite>.
 * '''ERK1/2''' phosphorylate PTPN12 at Serine-571 <cite>Zheng11</cite>.
-* [http://en.wikipedia.org/wiki/GRB2 Adaptor molecule '''Grb2'''] binds to PTPN12/PTP-PEST via two SH3 domains of Grb2 and proline-rich sequences of PTPN12. The interaction couples PTPN12 with growth factor receptors <cite>Charest97</cite>.
+* [http://en.wikipedia.org/wiki/GRB2 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 <cite>Charest97</cite>.
 * [http://en.wikipedia.org/wiki/Gelsolin '''Gelsolin'''], an actin-binding protein that is a key regulator of actin filament assembly and disassembly <cite>Chellaiah01</cite>.
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 * [http://en.wikipedia.org/wiki/LPXN '''Leupaxin'''] forms a signaling complex with PTPN12, Pyk2, and c-Src to regulate migration of prostate cancer cells <cite>Sahu07</cite>.
-* [http://en.wikipedia.org/wiki/Caspase_3 '''Caspase 3'''] specifically cleaves PTPN12/PTP-PEST at the (549)DSPD motif and therefore regulates PTPN12/PTP-PEST interactions with paxillin, leupaxin, Shc, and PSTPIP <cite>Halle07</cite>.
+* [http://en.wikipedia.org/wiki/Caspase_3 '''Caspase 3'''] specifically cleaves PTPN12 at the (549)DSPD motif and therefore regulates PTPN12 interactions with paxillin, leupaxin, Shc, and PSTPIP <cite>Halle07</cite>.
 * [http://en.wikipedia.org/wiki/PIN1 '''PIN1''' (Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1)] <cite>Zheng11</cite>
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 * JAK2 <cite>Horsch01</cite>
-PPTN12/PTP-PEST is implicated in cancer <cite>Takekawa94, Espejo10, Villa-Moruzzi11, Sun11, Cao12, Su13, Luo14, Harris14</cite>, particularly in regulating cell motility.
+PPTN12 is implicated in cancer <cite>Takekawa94, Espejo10, Villa-Moruzzi11, Sun11, Cao12, Su13, Luo14, Harris14</cite>, particularly in regulating cell motility.
 ===== PTPN18 (BDP1/PTP-HSCF) =====

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 ===Functions===
-PTPN12 has three human members, PTPN12/PTP-PEST, PTPN18/BDP, and PTPN22/LYP. They have different functions, though they share some common interacting partners and/or substrates.
+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 [http://www.gtexportal.org/home/gene/PTPN12 GTEx]. The expression pattern is consistent with earlier studies <cite>Yi91, Takekawa92, Yang93</cite>.
+PTPN12 is widely expressed in different tissues and at relatively low level in brain according to [http://www.gtexportal.org/home/gene/PTPN12 GTEx] <cite>Yi91, Takekawa92, Yang93</cite>.
-PTPN12 have the following substrates and/or interacting partners involved in lymphocyte activation, cytoskeleton organization etc.
+PTPN12 has the following substrates and/or interacting partners involved in lymphocyte activation, cytoskeleton organization etc.
 * [http://en.wikipedia.org/wiki/BCAR1 '''p130Cas/BCAR1'''] <cite>Garton96</cite>. p130Cas/BCAR1 is an adaptor protein that regulates multiple signaling pathways and implicated in cancers. PTPN12/PTP-PEST 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 <cite>Garton97, Garton99</cite>. PTPN12 also interacts with other members of the p130(Cas) family ('''Hef1''' and '''Sin''') via their SH3 domain in vitro <cite>Cote98</cite>.

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 #Hill02 pmid=11882361
 #Horsch01 pmid=11731619
 #Kim96 pmid=8950995
 #Kyogoku04 pmid=15273934