MAPKKKs

Mitogen-activated protein kinase (MAPK) signaling pathways mediate cellular responses to many stimuli including growth factors, hormones, cytokines and environmental stresses. MAPK pathways can be divided into those that predominantly respond to mitogens and those that predominantly respond to stress. The extracellular signal regulated kinase (ERK1 and ERK2) pathways are activated by mitogens and play an important role in controlling cell growth and differentiation. The stress-activated MAPK pathways include the c-Jun N-terminal kinase (JNK) and p38 pathways that are implicated in apoptosis and the immune response. The ERK5 MAPK pathway responds to both growth signals and certain stresses. All MAPK pathways feature a three-kinase cascade whereby MAPKs are activated by phosphorylation by a MAPK kinase (MKK or MEK) and MKKs are activated by serine/threonine phosphorylation by MAPK kinase kinases (MAPKKK or MAP3K).

The MAP3K group consists of a large diverse group of protein kinases with overlapping specificities for MKKs. They include members of the RAF, MEKK (MEK kinase), MLK (mixed lineage kinase), and TAO (thousand and one amino acid) families and the protein kinases MOS, ASK1 (apoptosis signal-regulating kinase-1), TAK1 (TGFβ-activated kinase-1) and TPL2 (tumor progression locus-2). The activities of MAP3Ks can be regulated by a number of mechanisms including phosphorylation, interaction with small GTPases, proteolysis, and binding to regulatory or scaffold proteins.

The RAF family are components of ERK signaling pathways and phosphorylate the highly related MEK1 and MEK2. RAF proteins are activated by their recruitment to Ras GTPase at membranes and by phosphorylation at regulatory sites. Mutations in RAF, particularly B-RAF, are associated with human cancers. A second MAP3K that is specific for the ERK pathway is MOS which is primarily expressed in germline cells and is implicated in oocyte maturation. The TPL2 MAP3K activates the ERK pathway and plays an important role in the innate immune response.

The MEKK and MLK families of MAP3Ks and the less well characterized TAO family are components of stress-activated MAPK pathways. The MEKK and MLK families can be activated by Rho-family GTPases and STE20-like protein kinases. MEKK1 can also be activated by proteolysis following apoptotic stimuli. Caspases cleave MEKK1 to release the catalytically active C-terminus that is highly pro-apoptotic. While predominantly involved in stress-signaling some members of these families can function as regulators of ERK pathways. For example, MEKK2 and MEKK3 are components of the ERK5 cascade, MEKK1 can function as a ubiquitin ligase and cause degradation of ERK1/2, and MLK3 has been suggested to be required for B-RAF signaling to ERK1/2.

Additional MAP3Ks that are components of JNK and p38 signaling pathways include ASK1 and TAK1. These MAP3Ks have distinct mechanisms of activation. ASK1 mediates apoptosis induced by oxidative stress and is activated by dissociation from a redox-sensitive inhibitory protein, thioredoxin. TAK1 is activated by TGFβ and cytokines via a mechanism dependent on the ubiquitination of an associated protein, TRAF6.

In addition to their central roles in MAPK signaling some MAP3Ks are components of other signaling pathways. For example C-RAF, MEKKs and TAK1 can activate the NF-kB signaling pathway independently of MAPKs. Also, a MAP3K related kinase NIK (NF-kB inducing kinase) is a component of NF-kB signalling pathways but has no reported role in MAPK signalling.

The large body of literature on MAPK pathways suggests that there is a high level of promiscuity at the level of MAP3Ks. However it is clear from gene-deletion studies in mice and lower eukaryotes that individual MAP3Ks have distinct cellular roles. One important regulatory mechanism for achieving specificity is by scaffold proteins linking particular MAP3Ks to particular MAPK modules in response to a stimulus.

 

The Table below contains accepted modulators and additional information. For a list of additional products, see the "Similar Products" section below.

 

Family Members RAF MOS MEKK MLK
Other Names Proto-oncogene serine-threonine protein kinase Proto-oncogene serine-threonine protein kinase Mitogen-activated protein kinase kinase kinase
MAP3K
Mitogen lineage kinase
Molecular
Weight
(kDa)
67 – 85 kDa 39 kDa 69 – 182 kDa 91 – 122 kDa
Isoforms A-RAF
B-RAF
C-RAF (RAF1)
Not Known MEKK1 (M6939) (MAP3K1)
MEKK2 (MAP3K2)
MEKK3 (MAP3K3)
MEKK4 (MTK1, MAP3K4)
MLK1 (MAP3K9)
MLK2 (MST, MAP3K10)
MLK3 (SPRK, PTK1, MAP3K11)
MLK4
MLK7 (ZAK, MRK, MLTK)
DLK (MUK, ZPK, MAP3K12)
LZK (MAP3K13)
Species Vertebrate
Fly
Worm
Vertebrate
Fly
Vertebrate
Fly
Worm
Yeast
Vertebrate
Fly
Worm
Domain
Organization
Ser/Thr-protein kinase domain
Cys-rich domain
Ubiquitin-like domain
Ras-binding domain
Ser/Thr-protein kinase domain Ser/Thr-protein kinase domain
Ring-ZF domain
Ras-binding domain
MEKK1
PH-domain (MEKK1, MEKK4)
CRIB (MEKK4)
Ser/Thr-protein kinase domain
Leucine-zippers domain
SH3 domain
CRIB domain (MLK1-4)
SAM domain (MLK7)
Phosphorylation
Sites
Ser214
Ser299
Tyr302
Thr452
Thr455
Ser582 (A-RAF)
Ser364
Ser445
Thr598
Ser601
Ser728 (B-RAF)
Ser43
Ser233
Ser259
Ser338
Tyr341
Thr491
Ser494
Ser621 (C-RAF)
Ser3 Thr1383
Thr1395 (MEKK1)
Thr523 (MEKK2)
Thr530 (MEKK3)
Thr1504 (MEKK4)
Thr277
Ser281 + 11 C-terminal sites (MLK3)
Tissue
Distribution
Ubiquitous Germ cells Ubiquitous Ubiquitous
Subcellular
Localization
Cytosol Cytosol Cytosol Cytosol
Binding
Partners/
Associated
Proteins
KSR1, 2
RKIP
CNK
BAG1
SUR8
Paxillin
14-3-3
Not Known LAD
OSM (O1637, O9635)
JLP
Mip1 (M6167M6292M6542M6417)
GADD45
JSAP1
TRAFs
14-3-3
JNKBP1
JIP1
JIP2
JIP3
MBIP
POSH
14-3-3
Upstream
Activators
RAS (R9894)
RAP1 (R2152)
PAK
CDC2-cyclin B RAS
RAC1
HPK1
CDC42
GCK
RIP
RAC1
CDC42
HPK1
PAK
Downstream
Activation
MEK1
MEK2
MEK1
MEK2
Myt1
MyoD
MEK1
MEK2
MKK3
MKK4
MKK5
MKK6 (M5814)
MKK7
IKK
MKK3
MKK4
MKK6 (M5814)
MKK7
Activators Growth factors Progesterone (P0130, P3972)
Growth factors
Stress
Cytokines
Growth factors
Stress
Cytokines
Growth factors
Inhibitors BAY-43-9006 Not Known Not Known CEP-1347
Selective
Activators
Not Known Not Known Not Known Not Known
Physiological
Function
Cell growth Oocyte maturation Stress responses
Development
Stress responses
Development
Neuronal apoptosis
Disease
Relevance
Cancer (B-RAF) Not Known Not Known Not Known

 

 

Family Members TAO ASK TAK1 TPL-2
Other Names PSK
JIK
KFC
Not Known MAP3K7 COT
MAP3K8
Molecular
Weight
(kDa)
105 – 138 kDa 112 – 155 kDa 67 kDa 58 kDa
Isoforms TAO1 (PSK2, KFC-B, MARRK)
TAO2 (PSK1, KFC-C)
TAO3 (JIK, KFC-A)
ASK1 (MAPKKK5, MAP3K5)
ASK2 (MAPKKK6, MAP3K6)
Not Known Not Known
Species Vertebrate
Fly
Worm
Vertebrate
Fly
Worm
Vertebrate
Fly
Worm
Vertebrate
Domain
Organization
Ser/Thr-protein kinase domain Ser/Thr-protein kinase domain Ser/Thr-protein kinase Ser/Thr-protein kinase
Phosphorylation
Sites
Not Known Ser83
Thr838 (ASK1)
Thr187
Ser192
Thr290
Ser400
Tissue
Distribution
Ubiquitous Ubiquitous Ubiquitous Ubiquitous
Subcellular
Localization
Cytosol Cytosol Cytosol Cytosol
Binding
Partners/
Associated
Proteins
Tubulin β-Arrestin-2
TRAF2
CDC25A
Thioredoxin (T0910, T3658)
AIP1
SKRP1
Daxx
Nef
14-3-3
JIP3
TAB1, 2, 3
SMAD3
TRAF6
SEF
RKIP
NF-kB1/p105
AKT (A8729, A9104)
KSR2
ABIN-2
TRAF2
Upstream
Activators
Not Known CaMKII
IRE1
K63-polyubiquitination Not Known
Downstream
Activation
MKK3
MKK4
MKK6 (M5814)
MKK7
MKK3
MKK4
MKK6 (M5814)
MKK7
MKK3
MKK4
MKK6 (M5814)
IKK
HIPK2
MEK1
MEK2
MKK4
MKK5
MKK6 (M5814)
NIK
Activators Carbachol
Osmotic stress
Stress
Calcium
GPCR
Stress
Cytokines
Wnt
TGF-β
Cytokines
LPS (L2630)
Inhibitors Not Known Not Known Not Known Not Known
Selective
Activators
Not Known Not Known Not Known Not Known
Physiological
Function
Stress responses Stress responses
Neuronal apoptosis
Heart function
Stress responses Inflammation response
Disease
Relevance
Not Known Not Known Not Known T-cell lymphoma

 

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References