Development - PDGF signaling via STATs and NF-kB

PDGF-induced anti-apoptosis and proliferation of cells via STAT and NF-KB pathways

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, PDGF-A and PDGF-B, and two only recently discovered chains, PDGF-C and PDGF-D. The four PDGF chains assemble into disulphide-bonded dimers via homo- or heterodimerization.

PDGFs regulate biological functions in cells through binding to specific structurally related high-affinity receptors (PDGFR) on cell surface, denoted PDGFR alpha and beta. Upon ligand binding, the PDGFR dimerizes and autophosphorylates on a number of tyrosine residues. Tyrosine phosphorylated sites are used by PDGFR as anchor sites for various SH2 domain-containing proteins [1].

PDGF is a principal survival factor that inhibits apoptosis and promotes proliferation. The mechanisms of cellular 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].

It is show, that PDGF-B [3], [4] and sometimes PDGF-A [5] regulate of cell growth and survival via the Signal transducer and activator of transcription (STAT) pathway [6] and/or of through Nuclear factors of kappa light polypeptide in B-cells (NF-KB) [2]. PDGFR-beta and, to a lesser degree, PDGFR-alpha participate in these processes [7].

Activated PDGFRs directly [8], [9] or indirectly (via activate members of the Janus kinase family (JAK) including JAK1/JAK2 and/or Tyrosine kinase 2 (TYK2) [10], [11], [12]. JAK1/JAK2 or TYK2 signaling then lead to the stimulation of members of the STAT family (STAT1, STAT3, STAT5, STAT6). However, STAT3 may also be stimulated by the proto-oncogene tyrosine-protein kinase (c-Src) and the Double-stranded RNA-activated protein kinase (PKR). PKR is pre-associated with STAT3 and PDGFR-beta. It may facilitate tyrosine phosphorylation of STAT3 by c-Src [13].

Activated STATs participate in the survival and development of cells by regulating the expression of several genes such as proto-oncogene proteins c-Fos and c-Myc [13], [14].

Upon PDGF stimulation, PDGFRs activate Phosphatidylinositol 3-kinase (PI3K) directly or indirectly (via Src homology 2 domain containing transforming protein (Shc)/ Factor receptor bound 2 (Grb2). The PI3K regulatory subunit (PI3K reg 1A) stimulates activity of PI3K catalytic subunits (PI3K cat 1A), which in turn catalyzes of reaction conversion Phosphatidylinositol-4,5-biphosphate (PtdIns(4,5)P2) into Phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3). PtdIns(3,4,5)P3 binds to the pleckstrin-homology domain of serine/threonine protein kinase Akt, to recruit Akt to the plasma membrane. When Akt transiently associates with Inhibitor of nuclear factor kappa B kinase catalytic subunits (IKK), it phosphorilates and activates IKK. IKK phosphorylates and markes for degradation of NF-KB inhibitor (I-KB), thereby inducing NF-kB DNA-binding activity.

However, under certain circumstances, Akt can activate NF-KB through a mechanism that does not involve I-KB degradation by modulating the transcriptional potential of transcription factor p65 (RelA). RelA is a component of NF-KB complex [2].

NF-KB regulates transcription of c-Myc. c-Myc is a central regulator of cell growth, death and differentiation. c-Myc is required for cell proliferation but, in the absence of survival factors, it induces apoptosis. Thus, PDGF stimulates c-Myc-mediated proliferation by activating the H-Ras/PI3K/Akt pathway [2].

References:

1. Fredriksson L, Li H, Eriksson U
   The PDGF family: four gene products form five dimeric isoforms. Cytokine & growth factor reviews 2004 Aug;15(4):197-204
2. Romashkova JA, Makarov SS
   NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling. Nature 1999 Sep 2;401(6748):86-90
3. Yellaturu CR, Rao GN
   Cytosolic phospholipase A2 is an effector of Jak/STAT signaling and is involved in platelet-derived growth factor BB-induced growth in vascular smooth muscle cells. The Journal of biological chemistry 2003 Mar 14;278(11):9986-92
4. Neeli I, Liu Z, Dronadula N, Ma ZA, Rao GN
   An essential role of the Jak-2/STAT-3/cytosolic phospholipase A(2) axis in platelet-derived growth factor BB-induced vascular smooth muscle cell motility. The Journal of biological chemistry 2004 Oct 29;279(44):46122-8
5. Dell'Albani P, Kahn MA, Cole R, Condorelli DF, Giuffrida-Stella AM, de Vellis J
   Oligodendroglial survival factors, PDGF-AA and CNTF, activate similar JAK/STAT signaling pathways. Journal of neuroscience research 1998 Oct 15;54(2):191-205
6. Shen Y, Devgan G, Darnell JE Jr, Bromberg JF
   Constitutively activated Stat3 protects fibroblasts from serum withdrawal and UV-induced apoptosis and antagonizes the proapoptotic effects of activated Stat1. Proceedings of the National Academy of Sciences of the United States of America 2001 Feb 13;98(4):1543-8
7. Valgeirsdottir S, Paukku K, Silvennoinen O, Heldin CH, Claesson-Welsh L
   Activation of Stat5 by platelet-derived growth factor (PDGF) is dependent on phosphorylation sites in PDGF beta-receptor juxtamembrane and kinase insert domains. Oncogene 1998 Jan 29;16(4):505-15
8. Vignais ML, Sadowski HB, Watling D, Rogers NC, Gilman M
   Platelet-derived growth factor induces phosphorylation of multiple JAK family kinases and STAT proteins. Molecular and cellular biology 1996 Apr;16(4):1759-69
9. Paukku K, Valgeirsdottir S, Saharinen P, Bergman M, Heldin CH, Silvennoinen O
   Platelet-derived growth factor (PDGF)-induced activation of signal transducer and activator of transcription (Stat) 5 is mediated by PDGF beta-receptor and is not dependent on c-src, fyn, jak1 or jak2 kinases. The Biochemical journal 2000 Feb 1;345 Pt 3:759-66
10. Patel BK, Wang LM, Lee CC, Taylor WG, Pierce JH, LaRochelle WJ
    Stat6 and Jak1 are common elements in platelet-derived growth factor and interleukin-4 signal transduction pathways in NIH 3T3 fibroblasts. The Journal of biological chemistry 1996 Sep 6;271(36):22175-82
11. Choudhury GG, Marra F, Kiyomoto H, Abboud HE
    PDGF stimulates tyrosine phosphorylation of JAK 1 protein tyrosine kinase in human mesangial cells. Kidney international 1996 Jan;49(1):19-25
12. Vignais ML, Gilman M
    Distinct mechanisms of activation of Stat1 and Stat3 by platelet-derived growth factor receptor in a cell-free system. Molecular and cellular biology 1999 May;19(5):3727-35
13. Deb A, Zamanian-Daryoush M, Xu Z, Kadereit S, Williams BR
    Protein kinase PKR is required for platelet-derived growth factor signaling of c-fos gene expression via Erks and Stat3. The EMBO journal 2001 May 15;20(10):2487-96
14. Simon AR, Takahashi S, Severgnini M, Fanburg BL, Cochran BH
    Role of the JAK-STAT pathway in PDGF-stimulated proliferation of human airway smooth muscle cells. American journal of physiology. Lung cellular and molecular physiology 2002 Jun;282(6):L1296-304