STE20

The Ste20 (Sterile 20) protein kinase family consists of enzymes with sequence homology to the yeast MAP4K Ste20p in the pheromone response pathway. Based on phylogenetic relationships, they can be divided into two subfamilies: PAK (p21-activated kinase) and GCK (germinal center kinase). The PAKs include six kinases that contain a C-terminal catalytic domain and an N-terminal regulatory domain with a small G protein binding motif. The GCKs include 24 kinases that contain an N-terminal catalytic domain and a C-terminal noncatalytic region with a wide variety of structures. Many Ste20 kinases activate mitogen-activated protein kinase (MAPK) pathways, among which the most studied are the ERK1/2, JNK and p38 cascades. These signal transduction pathways regulate gene transcription, cell cycle, apoptosis, proliferation, differentiation etc. Some Ste20 kinases phosphorylate and activate one or more MAP3Ks directly; thus they are MAP4Ks in MAPK pathways. Others activate MAPK pathways through protein-protein interactions, independent of their catalytic activities. Ste20 kinases have also been implicated in regulation of NF-kB, cytoskeletal rearrangements, and cell polarity.

The PAK subfamily, which shares many characteristics with yeast Ste20p, can be further divided into two groups: PAK-I (PAK-1, 2 and 3) and PAK-II (PAK-4, 5 and 6). The group I PAKs are activated by GTP-bound small G proteins Cdc42 and Rac, but not by Ras or Rho. They can positively regulate the ERK1/2 MAPK pathway through at least two mechanisms. First, PAK2 phosphorylates Raf-1, a MAP3K, on Ser338. This phosphorylation is required for Ras activation of Raf-1 and is usually PI-3 kinase dependent. Second, PAK1 phosphorylates MEK1, a MAP2K, on Ser298, which is important for the interaction between Raf-1 and MEK1. In contrast, the group II PAKs contain higher basal kinase activity and are not further activated by small G proteins. However, binding of GTP-bound Cdc42 causes subcellular relocalization of PAK4 and 5. Both PAK groups regulate cytoskeletal rearrangements, although through different mechanisms. Several PAKs have also been implicated in anti-apoptotic processes.

The GCK subfamily can be divided into eight groups: GCK-I to GCK-VIII. Given the large number of these kinases, only a few representatives are discussed here. GCK in group I, plays an essential role in mediating the signal from TNF-α to the JNK MAPK pathway. The binding of TNF-α to its receptor induces the formation of a protein complex containing GCK, which binds to MEKK1, the MAP3K, leading to its activation. GCK activation of MEKK1 is apparently independent of its catalytic activity. MST1 in GCK-II group causes apoptosis when expressed in mammalian cells. MST1 first activates caspases and itself is cleaved by caspases to form a positive feedback loop. The resulting MST1 kinase domain then activates both JNK and p38 to promote apoptosis. GCK-IV contains four mammalian members including HGK (NIK) that binds to the SH3-containing protein Nck through its proline-rich motif. HGK is activated by the ephrin receptor family and its Drosophila ortholog Misshapen functions downstream of the fly Nck homolog. Misshapen is also involved in the Wnt pathway downstream of its receptor. GCK-VI contains OSR1 and SPAK, homologs of a Drosophila Ste20 kinase Fray. SPAK activates the p38 pathway, while OSR1 is unable to activate any known MAPK pathways. OSR1 phosphorylates PAK1 in the N-terminal regulatory domain, which might reduce its activation by GTP-bound small G proteins. Both SPAK and OSR1 have been reported to interact with several cation chloride co-transporters including KCC3, NKCC1, and NKCC2. In contrast, TAOs in GCK-VIII, are genuine MAP3Ks in the p38 MAPK pathway. TAOs directly phosphorylate and activate MEK3/6, the MAP2Ks, and they are required for p38 activation by heterotrimeric G proteins.

 

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

 

Family Members PAK1 PAK4 GCK MST1 YSK1
Other Names a-PAK
p21-activated kinase 1
p21-activated kinase 4   Krs-2 SOK
Group PAK-I PAK-II GCK-I GCK-II GCK-III
Molecular Weight
(kDa)
61 kDa 64 kDa 97 kDa 56 kDa 48 kDa
Structural Data 545 aa 591 aa 819 aa 487 aa 426 aa
Isoforms PAK1-3
PAK4-6
GCK
HPK1
KHS1
  MST1
MST2
YSK1
MST3
MASK
Species Human Human Human Human Human
Domain
Organization
C-terminal kinase domain
PBD domain
AID domain
C-terminal kinase domain
PBD domain
N-terminal kinase domain
PEST motif
N-terminal kinase domain
Dimerization domain
Inhibitory domain
N-terminal kinase domain
Phosphorylation
Sites
Thr423
Thr84
Ser74 Not Known Thr183
Thr187
Thr174
Tissue
Distribution
Brain
spleen
Ubiquitous Ubiquitous Ubiquitous Ubiquitous
Subcellular
Localization
Focal adhesions Golgi membrane Cytosolic Focal adhesions
Golgi apparatus
Binding Partners/
Associated Proteins
Rac
Cdc42
PIX
OSR1
GEF-H1
Cdc42
Integrin
TRAF6 NORE
DAP4
GM130
Upstream
Activators
Cdc42-GTP
Rac-GTP
EGF (E9644)
LPA (L7260)
HGF (H9661)
Cdc42-GTP
TNFα (T6674)
TNFβ (T7799)
poly(IC)
LPS (L2630)
UV
Taxol
Caspases (C5482, C6607, C2854, C1224, C6357, C6482, C8726)
Oxidant stress
GM130
Downstream
Activation
MEK1
MLCK
RhoGDI
DLC1
BAD (B1682)
LIMK1
GEF-H1
MBP (M1891) H2B 14-3-3 ζ
Activators Not Known Not Known Not Known Not Known Not Known
Inhibitors NF2/merlin Not Known Not Known Not Known Not Known
Selective
Activators
Not Known Not Known Not Known Not Known Not Known
Physiological
Function
Cell motility
Neurogenesis
Angiogenesis
Cell survival
Transformation filopodia formation
Cell adhesion
Activation of JNK pathway Apoptosis Cell migration
Disease
Relevance
Cancer metastasis
AIDS
Cancer Not Known Not Known Not Known

 

 

Family Members HGK LOK OSR1 MYO3A TAO2
Other Names NIK Stk10
Lymphocyte-oriented kinase
Oxysterol-binding protein-related protein 1 Myosin IIIa PSK
Group GCK-IV GCK-V GCK-VI GCK-VII GCK-VIII
Molecular Weight
(kDa)
142 kDa 130 kDa 58 kDa 185 kDa 138 kDa
Structural Data 1239 aa 968 aa 527 aa 1616 aa 1235 aa
Isoforms HGK
TNIK
MINK
LOK
SLK
OSR1
SPAK
MYO3A
SNICK
TAO1
TAO2
TAO3/JIK
Species Human Human Human Human Rat
Domain
Organization
N-terminal kinase domain
Coiled-coil domain
CNH domain  
N-terminal kinase domain
Coiled-coil domain
N-terminal kinase domain
PF1/PF2 domains
N-terminal kinase domain
IQ motifs
N-terminal kinase domain
Phosphorylation
Sites
Thr187
Thr191
Ser438 Ser339 Ser1355 Ser181
Tissue
Distribution
Brain
testis
Spleen
thymus
bone marrow
Ubiquitous Retina
brain
testis
Brain
Subcellular
Localization
Cytosolic   Cytosolic
nuclear
Cytoskeleton Cytosolic
Binding Partners/
Associated Proteins
Nck
STAT3
MEKK1
Plk1 PAK1
NKCC1/2
Calmodulin (P1431)
Actin
MEK3
MEK6
Upstream
Activators
EphR Not Known Sorbitol (S1876)
Not Known Sorbitol (S1876)
Carbachol (C4382)
Downstream
Activation
STAT3 Plk1
H2A
PAK1 MBP (M1891) MEK3
MEK6
Activators Not Known Not Known Not Known Not Known Not Known
Inhibitors Not Known Not Known Not Known Not Known Not Known
Selective
Activators
Not Known Not Known Not Known Not Known Not Known
Physiological
Function
Cell migration
transformation
Cell adhesion
cell cycle
Not Known Morphogenesis of photoreceptors Activation of p38 pathway
Disease
Relevance
Tumorigenesis Not Known Not Known Progressive nonsyndromic hearing loss Prostate cancer

 

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References