Stem cell factor (SCF) is a growth factor with membrane bound and soluble forms. It is expressed by fibroblasts and endothelial cells throughout the body, promoting proliferation, migration, survival and differentiation of hematopoetic progenitors, melanocytes and germ cells.(Linnekin 1999, Ronnstrand 2004, Lennartsson and Ronnstrand 2006). The receptor for SCF is KIT, a tyrosine kinase receptor (RTK) closely related to the receptors for platelet derived growth factor receptor, colony stimulating factor 1 (Linnekin 1999) and Flt3 (Rosnet et al. 1991). Four isoforms of c-Kit have been identified in humans. Alternative splicing results in isoforms of KIT differing in the presence or absence of four residues (GNNK) in the extracellular region. This occurs due to the use of an alternate 5' splice donor site. These GNNK+ and GNNK- variants are co-expressed in most tissues; the GNNK- form predominates and was more strongly tyrosine-phosphorylated and more rapidly internalized (Ronnstrand 2004). There are also splice variants that arise from alternative usage of splice acceptor site resulting in the presence or absence of a serine residue (Crosier et al., 1993). Finally, there is an alternative shorter transcript of KIT expressed in postmeiotic germ cells in the testis which encodes a truncated KIT consisting only of the second part of the kinase domain and thus lackig the extracellular and transmembrane domains as well as the first part of the kinase domain (Rossi et al. 1991). Binding of SCF homodimers to KIT results in KIT homodimerization followed by activation of its intrinsic tyrosine kinase activity. KIT stimulation activates a wide array of signalling pathways including MAPK, PI3K and JAK/STAT (Reber et al. 2006, Ronnstrand 2004). Defects of KIT in humans are associated with different genetic diseases and also in several types of cancers like mast cell leukaemia, germ cell tumours, certain subtypes of malignant melanoma and gastrointestinal tumours.
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Wakioka T, Sasaki A, Mitsui K, Yokouchi M, Inoue A, Komiya S, Yoshimura A.; ''APS, an adaptor protein containing Pleckstrin homology (PH) and Src homology-2 (SH2) domains inhibits the JAK-STAT pathway in collaboration with c-Cbl.''; PubMedEurope PMC
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Sun J, Pedersen M, Rönnstrand L.; ''Gab2 is involved in differential phosphoinositide 3-kinase signaling by two splice forms of c-Kit.''; PubMedEurope PMC
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Argetsinger LS, Stuckey JA, Robertson SA, Koleva RI, Cline JM, Marto JA, Myers MG, Carter-Su C.; ''Tyrosines 868, 966, and 972 in the kinase domain of JAK2 are autophosphorylated and required for maximal JAK2 kinase activity.''; PubMedEurope PMC
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Heissig B, Hattori K, Dias S, Friedrich M, Ferris B, Hackett NR, Crystal RG, Besmer P, Lyden D, Moore MA, Werb Z, Rafii S.; ''Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand.''; PubMedEurope PMC
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Liu SK, McGlade CJ.; ''Gads is a novel SH2 and SH3 domain-containing adaptor protein that binds to tyrosine-phosphorylated Shc.''; PubMedEurope PMC
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Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007.
The RAS-RAF-MEK-ERK pathway regulates processes such as proliferation, differentiation, survival, senescence and cell motility in response to growth factors, hormones and cytokines, among others. Binding of these stimuli to receptors in the plasma membrane promotes the GEF-mediated activation of RAS at the plasma membrane and initiates the three-tiered kinase cascade of the conventional MAPK cascades. GTP-bound RAS recruits RAF (the MAPK kinase kinase), and promotes its dimerization and activation (reviewed in Cseh et al, 2014; Roskoski, 2010; McKay and Morrison, 2007; Wellbrock et al, 2004). Activated RAF phosphorylates the MAPK kinase proteins MEK1 and MEK2 (also known as MAP2K1 and MAP2K2), which in turn phophorylate the proline-directed kinases ERK1 and 2 (also known as MAPK3 and MAPK1) (reviewed in Roskoski, 2012a, b; Kryiakis and Avruch, 2012). Activated ERK proteins may undergo dimerization and have identified targets in both the nucleus and the cytosol; consistent with this, a proportion of activated ERK protein relocalizes to the nucleus in response to stimuli (reviewed in Roskoski 2012b; Turjanski et al, 2007; Plotnikov et al, 2010; Cargnello et al, 2011). Although initially seen as a linear cascade originating at the plasma membrane and culminating in the nucleus, the RAS/RAF MAPK cascade is now also known to be activated from various intracellular location. Temporal and spatial specificity of the cascade is achieved in part through the interaction of pathway components with numerous scaffolding proteins (reviewed in McKay and Morrison, 2007; Brown and Sacks, 2009). The importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011).
SCF exists as two alternatively spliced variants, a soluble form and a membrane-bound form differing in one exon (exon 6). Both isoforms are initially membrane bound with an extracellular domain, a transmembrane segment and an intracellular region. The longer isoform is rapidly cleaved to generate a 165 aa soluble protein knows as sSCF. The SCF transcript that lacks exon 6 encodes a glycoprotein that remains membrane-bound (mSCF). Both mSCF and sSCF are bioactive but different in their efficacy in c-kit activation. Proteases including matrix metalloprotease-9 (Heissig et al., 2002), Chymase-1 (Longley et al., 1997) and several members of the ADAMs family (Kawaguchi et al, 2007; Amour et al, 2002; Chesneau et al, 2003; Mohan et al, 2002; Roghani et al, 1999; Zou et al, 2004) have been suggested to have a role in the processing of sSCF.
sSCF exists as noncovalently associated homodimer composed of two monomers interacting head-to-head to form an elongated, slightly bent dimer. Dimerization of sSCF is a dynamic process and it may play a regulatory role in the dimerization and activation of KIT (Zhang et al, 2000; Philo et al, 1996).
SOCS1 has been identified as a KIT binding partner from the yeast two-hybrid system (Sepulveda et al, 1999). SOCS1 expression is induced upon KIT activation. It associates with KIT via its SH2 domain. SOCS1 does not inhibit KIT kinase activity directly, instead it binds to GRB2 and VAV1, and selectively inhibits SCF-induced proliferation, while not effecting survival signal (Sepulveda et al, 1999). It has been proposed that SOCS1 may interrupt signal transduction pathways downstream of JAK2 (Sepulveda et al, 1999).
Vav1, once activated by PIP3 binding and phosphorylation by Src kinases, stimulates the GDP/GTP exchange activity of Rac. Vav1 is selective for Rac and catalyses exchange of bound GDP for GTP.
SCF induces rapid and transient autophosphorylation of JAK2 bound to c-KIT. JAKs bound to activated, dimerized receptors cross-phosphorylate and thereby activate each other. Multiple phosphorylation sites have been identified in JAK2 (tyrosines 221, 570, 868, 966, 972, 1007 and 1008 ) of which phosphorylation of tyrosine 1007 is essential for kinase activity (Feng et al 1997, Argetsinger et al. 2004, 2010). Tyrosine 1007 is in the activation loop and phosphorylation allows access of the catalytic loop to the ATP in the ATP binding domain. Of all the predicted phoshorylation sites only the critical tyrosine 1007 is represented in the reaction.
Tyrosine phosphatase PTPRO associates constitutively with c-Kit independently of SCF stimulation. PTPRO undergoes phosphorylation upon SCF stimulation. The PTPRO binding site on c-Kit and the molecular mechanism by which c-Kit signaling is regulated by PTPRO have not been determined.
GRB2 can be recruited indirectly to KIT through SHP2 (Tauchi et al. 1994). Y279, Y304, Y546 and Y584 (usually referred to as Y542 and Y580 in literature based on the SHP2 short isoform) are the potential sites of SHP2 tyrosyl phosphorylation and that Y546 is the major GRB2 binding site (Feng, et al. 1993, Araki, et al. 2003). This brings Grb2:SOS1 into proximity with the plasma membrane, where it can activate Ras.
Janus kinase 2 (JAK2) plays an important role in SCF induced proliferation (Radosevic et al. 2004). JAK2 was observed to pre-associate with KIT, with increased association after SCF stimulation of KIT (Weiler et al. 1996).
Activation of KIT mediates the recruitment of and association with STAT1alpha, STAT3, STAT5A and STAT5B (Deberry et al. 1997, Brizzi et al. 1999, Rönnstrand 2004).
Once recruited to the membrane in response to c-Kit stimulation, Son of sevenless (SOS1) activates the small GTPase protein Ras. SOS1 is a dual specificity guanine nucleotide exchange factor (GEF) that regulates both Ras and Rho family GTPases. SOS1 activates Ras by binding which induces a conformational change that causes the exchange of GDP with GTP. Ras proteins are membrane-bound GTPases that regulate crucial cellular processes such as growth, proliferation and differentiation. Active Ras-GTP stimulates multiple effector proteins such as Raf-1, which induce a variety of cellular responses, including initiation of mitogen activated protein kinase (MAPK) cascade signaling.
Following association with KIT, Tauchi et al. had observed phosphorylation of SHP2 (Tauchi et al. 1994). Tyrosine residues Y546 and Y584 (usually referred to as Y542 and Y580 in literature based on the short isoform) are the major sites of SHP2 tyrosyl phosphorylation. Src family kinases (SFKs) are candidates for this phosphorylation (Araki et al. 2003). The phosphorylated tyrosine residues on SHP2 can recruit the adapter protein GRB2 (Tauchi et al. 1994), but it is unclear whether GRB2 binding to SHP2 is important for KIT mediated SHP2 signaling or whether the effect of SHP2 on the RAS/ERK pathway goes through its catalytic activity.
Adapter proteins GADS, GRAP, GRB7 and GRB10 interact with activated KIT (Liu & McGlade 1998, Feng et al. 1996, Thömmes et al. 1999, Jahn et al. 2002).
APS bound to KIT is phosphorylated by tyrosine kinases in response to SCF stimulation (Wollberg et al, 2003). The C-terminal tyrosine 629 may be the target site of phosphorylation in APS (Wakioka et al, 1999).
Protein kinase C (PKC) alpha phosphorylates and regulates the activity of several receptor tyrosine kinases including KIT. PKC alpha is involved in a negative feedback loop regulating SCF induced proliferation by phosphorylating and inhibiting the kinase activity of KIT (Blume-Jensen et al. 1994, 1995). PKC alpha phosphorylates KIT on S741 and S746 of the kinase insert (Blume-Jensen et al. 1995). This serine phosphorylation inhibits KIT kinase activity and reduces the capacity of multiple SH2 containing signaling components to associate with KIT (Linnekin 1999).
PI3 kinases catalyze the production of phosphatidylinositol-3, 4, 5-triphosphate (PIP3) by phosphorylating phosphatidylinositol-4, 5-bisphosphate (PIP2). PIP3 bound to the inner lipid bilayer of the plasma membrane promotes the recruitment and activation of AKT. Active AKT subsequently phosphorylates the pro-apoptotic factor Bad at Ser136 which leads to it binding 14-3-3 protein and sequestering from the anti-apoptotic molecules Bcl-XL therby reducing antiapoptotic events and promoting cell survival. The alternative route for c-Kit mediated survival is through AKT-mediated phosphorylation and incativation of the forkhead transcription factor (FoxO3a) (Engstrom et al, 2003; Lennartson et al , 2005).
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dimer:p-c-Kit:SFKs
complexproteins:p-KIT
complexThe importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011).
kinases:p-KIT
complexcomplex:p-STAT
dimersAnnotated Interactions
dimer:p-c-Kit:SFKs
complexdimer:p-c-Kit:SFKs
complexdimer:p-c-Kit:SFKs
complexproteins:p-KIT
complexProteases including matrix metalloprotease-9 (Heissig et al., 2002), Chymase-1 (Longley et al., 1997) and several members of the ADAMs family (Kawaguchi et al, 2007; Amour et al, 2002; Chesneau et al, 2003; Mohan et al, 2002; Roghani et al, 1999; Zou et al, 2004) have been suggested to have a role in the processing of sSCF.