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Src

Since the isolation of v-Src as the transforming component of Rous sarcoma virus, and the subsequent identification of its cellular homolog c-Src, there has been intense interest in its activity and regulation. Src is the founding member of a group of non-receptor protein tyrosine kinases termed the Src family kinases (SFKs). All members share a basic mutidomain structure and a high degree of homology. SFKs can be further subdivided into a core group of “typical” SFKs which in humans consists of eight members (Src, Blk, Fgr, Fyn, Hck, Lck, Lyn, and Yes), a small group of “atypical” members (Brk, Frk and Srm), and two closely related kinases (Csk and Matk), that regulate the typical SFKs.

Typical SFKs are defined by the presence of five domains: a unique region of variable length, containing at its extreme amino-terminus motifs specifying modification by the short fatty acids palmitate and/or myristate; an SH3 domain, which mediates binding to specific PXXP motifs; an SH2 domain which governs binding to specific phosphotyrosine residues; a catalytic domain containing a tyrosine in the activation loop whose phosphorylation modulates catalytic activity; and a short carboxy-terminal tail with a tyrosine residue whose phosphorylation negatively regulates the enzyme. The atypical members all share a similar core structure, although none have the motif required for myristylation, and while Frk and Brk have a regulatory tyrosine in the C-tail, Srm does not. In addition, all atypical members have a nuclear localization sequence in the SH2 domain. The regulators Csk and Matk lack myristylation motifs, activation loop tyrosines and C-terminal regulatory tails.

The activity of typical SFKs is exquisitely regulated by structural constraints. They are usually held in a “closed” inactive form, and transition to an “open” active conformation upon a stimulus. For example, Src in the inactive form is phosphorylated in the C-terminal tail (tyrosine 530), a reaction usually carried out by Csk. This phosphorylation favors interaction between the tail and the SH2 domain which, together with a second intramolecular interaction between the SH3 domain and sequences linking the SH2 domain and the kinase domain, promotes the closed conformation. The SH2 and SH3 domains are masked, and the conformation of the kinase domain is unfavorable for catalysis. Transition to the active state can occur via either dephosphorylation of the tail tyrosine or by the binding of high affinity ligands to the SH2 and/or SH3 domains.

SFKs are frequently activated when extracellular ligands associate with their cognate receptors (such as receptor tyrosine kinases, G-protein coupled receptors, integrin receptors and immune recognition receptors) as well as intrinsically during mitosis. SFKs participate in mitogenesis, cell survival, cytoskeletal reorganization and motility, as well as specialized functions such as immune cell development, neuronal cell signaling, osteoclast and platelet function etc. In addition, deregulation and/or overexpression of both typical and atypical SFKs have been implicated in cancer causation. In keeping with the involvement of SFKs in many signaling pathways, a large and growing number of SFK substrates are being identified (currently more than 50 for Src alone).

Several small molecule inhibitors of SFKs have been identified, of which two (PP2 and SU6656) are generally available. PP2 displays considerable selectivity for SFKs and can inhibit Lck and Fyn in the nanomolar range; however it is an equally potent inhibitor of the PDGF receptor and other RTKs, as well as Tec kinases. SU6656 inhibits SFKs in the high nanomolar range, and does not inhibit the PDGF receptor or Tec, but it is very unlikely to be totally selective for SFKs. Where possible, results obtained with an SFK should be confirmed with a second inhibitor, or using other means.

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

 

Family Members Src Blk Fgr Fyn Hck
Other Names c-Src
pp60c-Src
  Src2
p55c-fgr
p59Fyn
Slk/Syn
JTK9
Group          
Molecular Weight
(kDa)
59.8 57.7 59.4 60.7 57.3
Structural Data 536 505 529 537 526
Isoforms nSrc Not Known Not Known Fyna, Fynb, Fync p59Hck, p61Hck
Species Avian (v-Src), human, monkey, mouse, Xenopus, rat, chordite Human, mouse, rat Human, mouse, rat Human, mouse, rat, Xenopus Human, monkey, mouse, rat
Domain
Organization
SH3-SH2-Tyr kinase SH3-SH2-Tyr kinase SH3-SH2-Tyr kinase SH3-SH2-Tyr kinase SH3-SH2-Tyr kinase
Phosphorylation
Sites
Ser12
Ser17
Tyr216
Tyr419
Tyr530
Tyr389
Tyr501
Tyr523
Tyr412
Tyr531
Tyr420
Tyr522
Tyr390
Tissue
Expression
Ubiquitous B cells Myeloid cells
B cells
Ubiquitous Myeloid cells
Subcellular
Organization
Cytoplasm, plasma membrane Cytoplasm Cytoplasm Cytoplasm, plasma membrane Cytoplasm, plasma membrane
Binding Partners/
Associated Proteins
ADAM12
Csk
EGFR
FKHR
Sam68
Paxillin
WASp
14-3-3 β/γ/ε
PKCε/ζ
Bcl2
CBL
PLCγ2
Ubiquitin protein ligase E3A
CCR3
CD24
SLAM
SHIP
WASp
PI3K (p85α)
Fyn-binding protein
SLAM
SAP
Paxillin
WIP
Abl
p130Cas
Upstream
Activators
ErbB1; AP-1
PDGFR
IR
AMPK
Neu
Fibronectin
FGR
VDR
PI3K/Akt/eNOS pathway
LPS
IFNγ
AML1
BSAP/PAX5
NERF/ELF-2
NFkB
BSAP
EBF
Antigen receptor complex
Negative regulato of PP1a
Chemokine signaling
PMN adhesion
Urokinase
CD95L
NSAIDs
RAFTK
FAK
Vav
PDGFR
Actin
Downstream
Activation
EGFR
Shc
Dynamin
Clathrin
Raf-1
JAK1
STAT1/3/5
Tks5
G protein-linked receptor kinase 2
Caveolin-1
Not Known PI3K
p120/130
Cbl
Pyk2
p190RhoGAP
Rac
PI3K
p120/130
Cbl
Pyk2
Ca2+
MAPK
Activators Growth factors Not Known Not Known Not Known Not Known
Inhibitors PP1
PP2
SU6656
Not Known Not Known PP1
PP2
SU6656
PP1
PP2
Physiological
Function
Cellular proliferation and differentiation, bone remodelling B lymphoid cell signal transduction Cellular migration and adhesion Synaptic plasticity, implicated in learning and memory, cellular growth May contribute to meutrophil migration and may regulate the degranulation process of neutrophils
Disease
Relevance
Embryonic development, multiple cancers, osteoporosis Some leukemias B-cell acute lymphoblastic leukemia Neurological disease – impaired special learning B-cell acute lymphoblastic leukemia

 

 

Family Members Lck Lyn Yes Csk Matk
Other Names   JTK8 c-yes
p61yes
  Chk
Ctk
Hyl
Group          
Molecular Weight
(kDa)
58.0 58.5 60.8 50.7 56.5
Structural Data 509 512 (Lyna)
491 (Lynb)
543 450 507
Isoforms Not Known Lyna, Lynb Not Known Not Known Matka, Matkb
Species Human, monkey, mouse, rat Human, monkey, mouse, rat Avian (v-Yes), human, monkey, mouse, rat, fish, Xenopus Human, monkey, mouse, rat Human, monkey, mouse, rat
Domain
Organization
SH3-SH2-Tyr kinase SH3-SH2-Tyr kinase SH3-SH2-Tyr kinase SH3-SH2-Tyr kinase SH3-SH2-Tyr kinase
Phosphorylation
Sites
Tyr505
Tyr394
Tyr508
Tyr397
Tyr537
Tyr426
Not Known Not Known
Tissue
Expression
T cells Myeloid cells
B cells
Ubiquitous Ubiquitous Hematopoietic
brain
Subcellular
Organization
Plasma membrane Cytoplasmic membrane
Cytoplasm (endocytic vesicles and coated pits)
Cytoplasmic membrane Cytoplasmic membrane Cytoplasm
Binding Partners/
Associated Proteins
ADAM15
p130Cas Cbl
Fas receptor
Jak3
Sam68
PI3K
SHP1
Jak2
Shc
Slp-76
YAP
Occludins
CD36
kAK2
PP2A
PyK2
p120GAP
Fyn
Cbl
IGF-1R
Src
PyK2
Paxillin
HER2/Neu
c-Kit
Upstream
Activators
CD4
CD8
Integrin (αIIb β3) LTB4
Et-1
PDGFR
CSF1R
Neu
FGR
GM-CSF
H2O2 Thrombin
Downstream
Activation
p56dok
p62dok
Zap-70
PLCγ1
NFAT
Btk
Syk
Cbl
PI3K (p85α)
PyK2
CD46
Not Known Not Known
Activators Not Known Not Known Not Known PP1
PP2
Not Known
Inhibitors PP1
PP2
Not Known PP1
PP2
SU6656
Not Known Not Known
Physiological
Function
T-Cell activation Mast cell adhesion Neutrophil degranulation, cellular proliferation, cell-cell interactions Negative regulators of SFK Negative regulators of SFK, hematopoietic cell signal transduction, inhibitory role in T cell proliferation
Disease
Relevance
Some leukemias Glomerulonephritis, IgM hyperglobulinemia Colon carcinomas, hematopoietic disorders Colorectal cancer Possible role in breast cancer

 

 

Family Members Brk Srm Frk MST1 YSK1
Other Names Ptk6 Srms: Src-related kinase lacking C-terminal regulatory tyrosine and N-terminal myristylation sites Rak
Gtk (rat)
Iyk (mouse)
Krs-2 SOK
Group       GCK-II GCK-III
Molecular Weight
(kDa)
51.8 54.8 58.3 56 48
Structural Data 451 488 505 487 426
Isoforms Not Known Not Known Not Known MST1, MST2
YSK1, MST3, MASK
Species Human, monkey, mouse, rat Human, monkey, mouse, rat, avian Human, monkey, mouse, rat Human Human
Domain
Organization
SH3-SH2-Tyr kinase SH3-SH2-Tyr kinase SH3-SH2-Tyr kinase N-terminal kinase domain
Dimerization domain
Inhibityory domain
N-terminal kinase domain
Phosphorylation
Sites
Tyr342
Tyr447
Tyr380 Tyr387
Tyr497
Thr183
Thr187
Thr174
Thr191
Tissue
Expression
Predominantly epithelial Predominantly epithelial Predominantly epithelial Ubiquitous Ubiquitous
Subcellular
Organization
Cytoplasm, nucleus Cytoplasmic membrane, nucleus Nucleusr, perinuclear Cytosolic, nuclear
Cytosolic, nuclear
Binding Partners/
Associated Proteins
Sam68
Slm1
Not Known pRb NORE
DAP4
GM130
Upstream
Activators
EGF Not Known Not Known UV
Taxol
Caspases (C5482, C6607, C2854, C1124, C6357, C6482, C2978, C8726)
Oxidant stress
GM130
Downstream
Activation
STAP2/BKS
Rac1
Paxillin
Sam68
Not Known Not Known H2B 14-3-3 ζ
Activators Not Known Not Known Not Known Not Known Not Known
Inhibitors Not Known Not Known Not Known Not Known Not Known
Physiological
Function
May function as an intracellular signal transducer in epithelial tissue
cell migration
Not Known Regulation of cellular growth Apoptosis Cell migration, transformation
Disease
Relevance
Possible role in breast cancer Not Known Possible role in breast cancer and acute myelogenous leukemia Not Known Not Known

 

 

Family Members HGK LOK OSR1 MYO3A TAO2
Other Names NIK Stk10
Lymphocyte-oriented kinase protein 1
Oxysterol-binding protein-related
Myosin IIIa
PSK
Group GCK-IV GCK-V GCK-VI GCK-VII GCK-VIII
Molecular Weight
(kDa)
142 130, 58
185 Not Known 138
Structural Data 1239 968, 527
1616 Not Known 1235
Isoforms HGK, TNIK, MINK
LOK, SLK, OSR1, SPAK
MYO3A, SNICK
Not Known 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
Ser438
Ser339
Ser1355
Ser181
Tissue
Expression
Brain, testis
Spleen, thymus, bone marrow
Ubiquitous Retina, brain, testis
Brain
Subcellular
Organization
Not Known
Not Known
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) Not Known MEK3
MEK6
Activators Not Known Not Known Not Known Not Known Not Known
Inhibitors Not Known Not Known Not Known Not Known Not Known
Physiological
Function
Cell migration
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