Table 1: Phenotypical changes observed in MAP kinase knock-in and knock-out mice.

See text for details.





MAP kinase Synonym Chromosome in human (mouse) Model type Background Phenotype References
ASK1 MEKK5 6q22.33 (10) KO C57BL/6 attenuated blood flow recovery, cardiac hypertrophy,angiogenesis, arteriogenesis, and remodelling Tobiume et al., 2001,
Matsuzawa et al., 2002,
Nishitoh et al., 2002
Izumi et al., 2003
Izumi et al., 2005
Yamaguchi et al., 2003
A-Raf
Xp11.4-p11.2 (X) KO C57BL/6 or 129/SvEv neurological and intestinal anomalies; post-natal mortality Pritchard et al., 1996
KO C57BL/6 x 129OLA ~50% survivors; abnormal position of the limbs Pritchard et al., 1996
B-Raf
7q34 (6) Conditional KO not specified defect in placentation Galabova-Kovacs et al., 2006
KO C57BL/6 vascular defects during mid-gestation Wojnowski et al., 1997
Thyroid-specific ca KI
enlarged thyroid and higher prevalence of parathyroid carcinoma Knauf et al., 2005
ca KI (ubiquitous expression) C57BL/6 death during gestation Mercer et al., 2005
ca KI (somatic expression) C57BL/6 death within 4 weeks after birth. Abnormalities of liver, spleen and bone marrow, proliferative disorder, nonlymphoid neoplasia Mercer et al., 2005
Forebrain-specific KO 129/SVEv x SvEms Impaired hippocampal long-term potentiation and learning and memory Chen et al., 2006
Raf-1
3p25 (6) KO 129/SvEv; 129/SvExC57BL/6 embryonic lethality; defects in yolk sac, placenta, skin, liver, and lungs Wojnowski et al., 1998; Hüser et al., 2001; Mikula et al., 2001
KO MF-1 modestly higher platelet count ; 40% are viable for one month after birth; reduced size and body weight Kamata et al., 2004
dn KI 129 Ola/C57BL6 and 129 Ola/MF-1 no phenotype Hüser et al., 2001
cardiac muscle-specific KO C57BL/6J cardiac dysfunctions; increased number of apoptotic cardiomyocytes Yamaguchi et al., 2004
cardiac specific dn Raf-1 C57BL/6J high lethality after acute pressure; increase cardiomyocyte apoptosis Harris et al., 2004
epidermis-specific KO not specified slower wound healing due to delayed keratinocyte migration Ehrenreiter et al., 2005
LOK STK10 5q35.1 (11) KO C57BL/6 no phenotype Endo et al., 2000
MEKK1 MAP3K1 5q11.2 (13) KO C57/BL6 failure of eyelid closure Yujiri et al., 1998
KO C57/BL6 cardiac dysfunction resulting in higher mortality relative to wild-type Sadoshima et al., 2002
dn KI C57/BL6x129/SvEv no phenotype Sadoshima et al., 2002
dn KI C57/BL6 Most embryos died beyond E14.5 due to defective erythropoiesis Bonnesen et al., 2005
KO C57/BL6 suppressed intimal hyperplasia after cessation of blood flow Li et al., 2005
dn KI C57/BL6 born with open eyes and abnormal epithelial cells of the eyelid Zhang et al., 2003a
MEKK2 MAP3K2 2 (18) dn KI C57/BL6 hyperproliferation of T cells in response to TCR/CD3 stimulation Guo et al., 2002
KO TC-1 no phenotype Kesavan et al., 2004
KO R-1 lethal Garrington et al., 2000
MEKK3 MAP3K3 17q23.3 (11) KO not specified Embryos die due to impaired cardiovascular development Yang et al., 2000; Yang et al., 2001; Abbasi et al., 2005
heart-specific ca KI not specified cardiac hypertrophy and sudden death Unpublished results in Abbasi et al., 2005
MEKK4 MAP3K4 6 (17) KO C57BL/6 X 129/SvEv born with decreased Mendelian ration; no obvious phenotype Chi et al., 2004
KO C57BL/6 Neural tube defects; do not survive weaning age Chi et al., 2005
dn KI C57/BL6x129/SvEv Neural tube defects; skeletal mal-formation; male infertility Abell et al., 2005
MLK3 MAP3K11 11q13.1-q13.3 (19) KO C57BL/6J dorsal midline defect Brancho et al., 2005
MST1 KRS2=STK4 20q11.2-q13.2 (2) Heart-specific wt KI C57BL/6J cardiac dysfunctions; premature death Yamamoto et al., 2003



Heart-specific dn KI C57BL/6J protection against induced cardiac myocyte apoptosis Yamamoto et al., 2003
NIK MAP3K14 17q21 (11) KO 129/SvEv abnormal osteoclastogenesis and less bone erosion; Aya et al., 2005
KO 129/SvEv ablated response to osteoclastogenic stimuli Novack et al., 2003
NLK LAK1 17q11.2 (11) KO C57BL/6 premature death Kortenjann et al., 2001
KO 129Sv/Ev grotwh retared, neurological and haematopoietic abnormalities Kortenjann et al., 2001
PAK1 p65PAK 11q13-q14 (7) dn KI B6DF/J incomplete lobuloalveolar development Wang et al., 2003
ca KI in mammary gland C57BL/6 X DBA development of malignant mammary gland tumours Wang et al., 2006a
PAK3
Xq21.3-q24 (X) KO C57BL/6 X 129sc or CD1 X 129 sc abnormalities in long-lasting synaptic plasticity, learning and memory Meng et al., 2005
PAK4
19q13.2 (7) KO C57BL/6 embryonal lethality due to cardiac and neuronal abnormalities Qu et al., 2003
PAK5 PAK7 20p12 (2) KO C57BL/6 X 129/SvEv no phenotype Li and Minden, 2003
TAK1 MAP3K7 6q14-q21 (4) cardiac specific ca KI FVB/N X ICR die within 2 weeks after birth because of cardiac hypertrophy Zhang et al., 2000
epidermal-specific dn KI C57BL/6 and 129SvJ skin abnormalities and skin inflammation; mice die by postnatal day 7 Omori et al., 2006; Samaya et al. 2006
KO 129/SvEv x C57BL/6 embryonic mortality beyond E12.5; neural fold dysmorphologies Shim et al., 2005
KO C57BL/6 embryonic death beyond E10.5 Sato et al., 2005
B cell-specific KO not specified impaired B cell development and humoral immune responses Sato et al., 2005
T cell-specific KO not specified impaired thymocyte development and activation Liu et al., 2006
MEK1 MAP2K1, MEK1 15q22.1-q22.33 (9 36.0 cM) KO 129/SvEv Reduced number of blood cells; anomalies in blood circulation or blood vessel formation; necrosis in various tissues Giroux et al., 1999
cardiac specific MEK1 not specified cardiac hypertrophy, resistance to ischemia/reperfusion-induced apoptosis Bueno et al., 2000
lens specific MEK1 C57BL/6J induced cataract formation Gong et al., 2001
skin-restricted MEK1 CBA × C57BL/6 ‘scruffy’ coats, epidermal hyperproliferation and hyperkeratosis Hobbs et al., 2004
MEK2 MAP2K2, MEK2 19p13.3 KO 129/SvEv Normal phenotype Belanger et al., 2003
MEK3 MAPK2K3, MEK3, SKK2 17q11.2 KO C57BL/6 Normal phenotype; normal numbers of thymocytes and splenocytes. Lu et al., 1999
Cardiac-specific dn MEK3 FVB/N enhanced cardiac hypertrophy Braz et al., 2003
MEK4 SKK1, MKK4, SEK1 17p12 KO C57BL/6 Embryos die between E10.5 and E12.5 All Mkk4-/- embryos were anemic Ganiatsas et al., 1998; Nishina et al., 1999; Brancho et al., 2003; Yang et al., 1997a
MEK5 MAP2K5, MKK5 6q22.33 KO C57BL/6 Embryonal heart defects. increased cell death in brains of E9.5 and E10.5 mek5-/- embryos. Wang et al., 2005b
MEK6 MAP2K6, SKK3 17q24.3 (11 E1) KO C57BL/6 Normal phenotype Tanaka et al., 2002
double KO (Mek3-/- Mek6-/-) C57BL/6 Mkk3-/- Mkk6-/- embryos died during midgestation at embryonic day 11.0-11.5 Brancho et al., 2003
chondrocytes-specific expressed MKK6 B6D2F1 Active MKK6 in chondrocytes showed a shortened axial and appendicular skeleton. Zhang et al., 2006
Cardiac-specific dn MEK6 FVB/N Mice showed enhanced cardiac hypertrophy Braz et al., 2003
MEK7 JNKK2, MEK7, SKK4
KO
Die during embryogenesis Dong et al.,2000
ERK1 MAPK3, p44MAPK, p44ERK1 16p11.2 (7 61.0 cM) KO 129/SvEv, C57BL/6 Normal phenotype Nekrasova et al., 2005 Pages et al., 1999
increase in locomotor activity; increase conditioned place preference to morphine Mazzucchelli et al., 2002
increase conditioned place preference to cocaine Ferguson et.al., 2006
decreased adiposity Bost et al., 2005
Th1 cell polarization and increased susceptibility to EAE Agrawal et al., 2006
ERK2 MAPK1 16 9.82 cM KO C57BL/6 Embryos die between before E8.5, abnormal morphology, failures in development of the extra-embryonic ectoderm and ectoplacental cone, placental abnormality Saba-El-Leil et al., 2003 Hatano et al., 2003
BALB/C embryonic lethality at E6.5; impaired mesoderm differentiation Yao et al., 2003
ERK5 MAPK6 17p11.2 (11 B2) KO BALB/c, C57BL/6 Embryos die at E11.5 due to problems in placental and blood vessel development Yan et al., 2003
JNK1
10q11.22(14) KO not specified Normal phenotype Dong et al., 1998
dnJNK1T183A/Y185F B10Br Defective deletion of DP thymocytes Rincon et al.,1998b
KO not specified increased Th2 cytokine production Dong et al.,2000
KO not specified/C57BL/6 increased Th2 cytokine production Yang et al.,1998
KO C57BL/6 suppressed MMP and bone destruction Han et al.,2001
JNK1/2KO not specified embryonic lethality due to defects in brain morphogenesis Kuan et al., 1999
JNK1/3KO not specified Normal phenotype Kuan et al., 1999
KO not specified not resistant to kainic acid Yang et al.,1997b
KO not specified promotes survival signals and preserves cardiac function in response to acute pressure overload Tachibana et al., 2006
JNK1 +/- KO/JNK2 KO C57BL/6 resistant to high fat diet Tuncman et al., 2006
KO C57BL/6 Normal phenotype Wang et al., 2006b
KO WT or IKK¯(¢hep) less susceptible to hepatocellular carcinoma Sakurai et al., 2006
KO C57BL/6 fewer cases of steatohepatitis Schattenberg et al.,2006
JNK2
5q35(11) KO not specified impaired T-cell activation Sabapathy et al.,1999a
KO not specified increased Th2 cytokine production Dong et al.,2000
KO not specified/C57BL/6 increased Th2 cytokine production Yang et al.,1998
KO C57BL/6 suppressed MMP and bone destruction Han et al.,2001
JNK2/3KO not specified Normal phenotype Kuan et al., 1999
KO not specified Normal phenotype Tachibana et al., 2006
JNK2 KO C57BL/6 become obese Tuncman et al., 2006
JNK1+/- /JNK2 KO C57BL/6 resistant to high fat diet Tuncman et al., 2006
KO C57BL/6 protected from liver injury; reduced mortality after toxin GalN administration Wang et al., 2006b
KO C57BL/6 no resistance to steatohepatitis Schattenberg et al.,2006
KO not specified not resistant to kainic acid Yang et al.,1997b
JNK3
4q22.1-q23(5) KO C57BL/6 resistant to kainic acid Yang et al.,1997b
JNK1/3KO not specified Normal phenotype Kuan et al., 1999
KO not specified Normal phenotype Tachibana et al., 2006
JNK2/3KO not specified Normal phenotype Kuan et al., 1999
p38® MAPK14; SAPK2a 6p21.3-p21.2 (17 13.5cM) KO different bg embryonic lethality due to placental defects Adams et al., 2000
KO different bg embryonic lethality due to placental defects Mudgett et al., 2000
KO (129/Svx129/J)F1xC57BL/6 embryonic lethality due to defects in erythroid differentation Tamura et al.,2000
KO-cardiac specific C57BL/6 reduced cardiac function, more severe in C57BL/6 Kaiser et al., 2004
p38+/- C57BL/6 resistant to myocardial infarction Otsu et al., 2003; Braz et al., 2003
Ko-p38floxed C57/BL6 different responses to biomechanical and ¯-adrenergic stress Nishida et al., 2004
KO-dnp38T180A/Y182F; cardiac specific Swiss Black increased resistance to infarction Ren et al.,2005
KO-dnp38 cardiac specific FVB/N died of cardiomyopathy Braz et al., 2003
KO-dnp38T180A/Y182F Black Swiss hypertrophic hearts; no fibrosis Zhang et al.,2003c
p38+/- C57BL/6 reduced contact hypersensitivity Takanami-Ohnishi et al., 2002
KO-dnp38T180A/Y182F under lck promoter B10Br impaired activation of Th1 Rincon et al.,1998a
p38+/- C57BL/6 disrupted renal structure and functional integrity in kidneys Maruyama et al., 2003
dn14-3-3/dnp38 KO Black Swiss resistant to cardiac pressure overload Zhang et al., 2003b
p38¯ MAPK11; SAPK2b 22q13.33(15) KO C57BL/6 Normal phenotype Beardmore et al., 2005; Turban et al., 2005
KO TNF¢ARE Normal phenotype Otsu et al., 2003
dn14-3-3/dnp38 KO Black Swiss resistant to cardiac pressure overload Zhang et al., 2003b
p38° MAPK12; SAPK3 22q13.33(15) KO C57BL/6xBALB/C blastocysts Normal phenotype Beardmore et al., 2005; Sabio et al.,2005
p38± SAPK4, MAPK13 6p21.3-p21.2 (17) KO C57BL/6xBALB/C blastocysts Normal phenotype Beardmore et al., 2005; Sabio et al.,2005
Mnk1/Mnk2
1p33(4)/19p13.3(10) KO C57BL/6 Normal phenotype Ueda et al.,2004
MSK1
14q31-q32.1(12) KO C57BL/6 altered response to cocaine induced locomotion and conditioning Brami-Cherrier et al., 2005
MSK2 RSK-B 11q11-q13(19) KO BALB/C Normal phenotype Wiggin et al., 2002
MK2 MAPKAPK2 1q32(1) KO C57BL/6 sensitive to high salt feeding,resistant to LPS-induced shock Gaestel, 2006; Kotlyarov et al., 1999
KO C57BL/6 reduced infarct size in brain and heart Shiroto et al., 2005
KO 129vxC57BL/6 reduced infarct size in brain and heart Wang et al., 2002
mk2/mk5KO not specified little resistant to LPS-induced shock Shi et al.,2003
KO DBA/ILacJ reduced severity, incidence and multiplicity to CIA Hegen et al., 2006
KO C57BL/6 Protects against cerulein induced pancreatitis Tietz et al., 2006
MK5 MAPKAPK5; PRAK 12q24.12-q24.13 (5) KO 129xC57BL/6 Normal phenotype Gaestel, 2006
KO C57/BL6 embryonic lethality Schumacher et al.,2004
mk2/mk5KO not specified little resistant to LPS-induced shock Shi et al.,2003