Development - PDGF signaling via MAPK cascades

PDGF signaling via MAPK cascades

Platelet-derived growth factors (PDGFs) are members of a large family of growth factors secreted by human vascular endothelial cells and fibroblasts.

The PDGF family is composed of four different polypeptide chains encoded by four different genes. There are two classical PDGF chains, Platelet-derived growth factor alpha and beta polypeptides (PDGF-A and PDGF-B), and two only recently discovered chains, Platelet derived growth factors C and D (PDGF-C, PDGF-D). The four PDGF chains assemble into homo- or heterodimers via disulphide bonds, and five different dimeric isoforms have been described so far; PDGF-AA, PDGF-AB, PDGF-BB, PDGF-CC and PDGF-DD.

PDGFs regulate biological functions in cells through binding to specific Platelet-derived growth factor receptor, alpha and beta polypeptides (PDGF-R-alpha, PDGF-R-beta) on the cell surface. The four dimeric isoforms, PDGF-AA, PDGF-AB, PDGF-BB and PDGF-CC can bind to and active PDGF-R-alpha, while PDGF-BB and PDGF-DD can specifically bind to and active PDGF-R-beta. PDGF-AB, PDGF-BB and PDGF-CC can also stimulate heterodimeric PDGF-R alpha/beta complexes [1].Upon ligand binding, PDGF-R-alpha and PDGF-R-beta dimerize and autophosphorylate on a number of tyrosine residues. Tyrosine phosphorylated sites are used by PDGF-receptor as anchor sites for various SH2 domain-containing proteins.

PDGF is a principal survival factor that inhibits apoptosis and promotes proliferation. The mechanisms of cell proliferation and transformation are intrinsically linked to the process of apoptosis: the default of proliferating cells is to undergo apoptosis unless specific survival signals are provided [2].

All types of PDGFs and PDGF-receptor may participate in proliferation of different cell types [3], [4], [5], [6] via Mitogen-activated protein kinases 8-10 (JNK(MAPK8-10)) [7] and Mitogen-activated protein kinase 1-3 (ERK1/2) cascades [8].

The JNK(MAPK8-10) cascade may be activated by phosphatidylinositol 3-kinase (PI3K) pathway [7], [9].

PDGF-receptor directly activates the Phosphoinositide-3-kinase, regulatory (PI3K reg class IA) and the catalytic (PI3K cat class IA) subunits. PI3K reg class IA stimulates the activity of PI3K cat class IA, which in turn converts inositol 4,5-biphosphate (PtdIns(4,5)P2) into inositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3). PtdIns(3,4,5)P3 stimulates Ras-related C3 botulinum toxin substrate 1 (Rac1) through guanine nucleotide exchange factors (e.g., Vav 2 guanine nucleotide exchange factor (VAV-2))[10].

Activated Rac1 stimulates Mitogen-activated protein kinase kinase kinase 1 (MEKK1(MAP3K1))/ Mitogen-activated protein kinase kinase 4 (MEK4(MAP2K4))/ JNK(MAPK8-10) pathway that leads to phosphorylation of the Jun oncogene (c-Jun) transcription factor. c-Jun induces activation of transcription of protein involved in cellular proliferation [8].

The ERK1/2 cascade may be activated by Growth factor receptor bound 2 (Grb2)/Son of sevenless homolog (Sos) pathway [7] and Phospholipase C gamma 1 (PLC-gamma 1) pathway [9].

Sos may be recruited to the membrane by forming complexes with SHC (Src homology 2 domain containing) transforming protein 1 (Shc)/ Grb2/ Sos or Grb2 /Sos. Activated Sos stimulates Harvey rat sarcoma viral oncogene homolog (H-Ras) by release of GDP [11]. In turn, this leads to the activation ERK1/2 via v-raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1)/ Mitogen-activated protein kinase kinases 1 and 2 (MEK1(MAP2K1) MEK2(MAP2K2)) pathway. In addition, c-Raf-1 may be phosphorylated via PLC gamma 1 pathway and PDGF-receptor can activate PLC-gamma 1 by phosphorylation. Activation of PLC-gamma 1 leads to the hydrolysis of PtdIns(4,5)P2, generation of diacylglycerol (DAG) and inositol trisphosphate (IP3) [12]. DAG and IP3 stimulate Protein kinases C alpha and epsilon (PKC-alpha, PKC- epsilon) [13], [14] and mobilize intracellular Ca('2+), respectively. PKCs in turn phosphorylate c-Raf-1.

ERK1/2 cascade may be inhibited by prostacyclin. Prostacyclin (which can be synthesized after PDGF stimulation [15]) binds to the Prostaglandin I2 (prostacyclin) receptor (Prostacyclin receptor), on the cell surface. Upon binding with prostacyclin, the receptor is stabilized in its active conformation and stimulates G-protein alpha-s. G-protein alpha-s acts as a signal transducers for activation of Adenylate cyclase 3 (adenylate cyclase III), which catalyzes the reaction of synthesis adenosine 3',5'-cyclic phosphate (cAMP) from adenosine-5'-triphosphate (ATP). The intracellular effects of cAMP in higher eukaryotes are primarily mediated by the activation of Protein kinase, cAMP-dependent, catalytic, alpha (PKA-cat alpha) [16].

Activated PKA-cat alpha phosphorylates v-raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1) and blocks binding between v-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-Ras) and c-Raf-1 and prevents participation c-Raf-1 in the activation of ERK1/2 signaling cascade [17].

Activation of the ERK1/2 cascade leads to phosphorylation of the ELK1, member of ETS oncogene family (Elk-1), which stimulates serum response factor (SRF). SRF activates transcription some protein which participate in proliferation of cells [18].

In addition, it has been previously show, that Janus kinase 2 (Jak2)/ signal transducer and activator of transcription (STAT) pathway may participate in cellular proliferation by regulating the expression of immediate-early genes, such as proto-oncogene v-myc myelocytomatosis viral oncogene homolog (c-Myc) [19].

References:

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