Pathway Map Details

Cytoskeleton remodeling_Role of PDGFs in cell migration



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PAK1, NET1, PDGF-C, PDGF-R-alpha, Tiam 1, CDC42, POR1, PDGF-B, PtdIns(3,4,5)P3, 2.7.1.153, PDGF receptor, PAK5, PDGF-D, PAK4, PtdIns(4,5)P2, N-WASP, VAV-2, RhoA, PI3K reg class IA (p85), VAV-1, Rac1, PDGF-R-beta, PDGF-A, PI3K cat class IA

Description:

Role of PDGFs in cell migration

Platelet-derived growth factors ( PDGF s) 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.

PDGF s 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. 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. 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].

All types of PDGF and PDGF-receptors may participate in cellular migration of different cell types [2], [3], [4] , although PDGF -BB is generally a stronger inducer this process than PDGF -AA.

Directed cell migration is a critical feature of several physiological and pathological processes, including development, wound healing, atherosclerosis, immunity, angiogenesis, and metastasis. The migratory response involves actin cytoskeleton reorganization, polarization, cell adhesion and detachment [5].

PDGF-receptor affect the actin cytoskeleton and cell migration through the Phosphoinositide-3-kinase, regulatory ( PI3K reg class IA ) and the catalytic ( PI3K cat class IA ) subunits. These subunits activate the small G-proteins of the Rho family (Cell division cycle 42 ( Cdc42 ), Ras-related C3 botulinum toxin substrate 1 ( Rac1 ) and Ras homolog gene family, member A ( RhoA )) [5].

PI3K reg class IA activates 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 Rac1 and RhoA through guanine nucleotide exchange factors (GEFs) (e.g., Vav 2 guanine nucleotide exchange factor ( VAV-2 )) [6], [7] or T-cell lymphoma invasion and metastasis 1 ( Tiam1 ) [8] )

Rac1 induces the formation of lamellipodia through ADP-ribosylation factor interacting protein 2 ( POR1) and/or via p21 protein (Cdc42/Rac)-activated kinase 1 ( PAK1 ) activation. Rho A induces formation of actin stress fibers and also controls cell polarization as well as cell adhesion [5].

In addition, PI3K reg class IA may stimulate of Cdc42 activation through GEFs such as Vav 2 guanine nucleotide exchange factor ( VAV-1 ) . Activated Cdc42 controls the formation of filopodia through some PAK s and Wiskott-Aldrich syndrome-like ( N-WASP ) activation.

In fact, RhoA induces a formation of focal adhesions, and Rac1/ CDC42 induce the formation of peripheral focal contacts [5].

The downstream effector of CDC42, PAK1 may contribute to the PDGF -induced disassembly of actin stress fibers and adhesion complexes. In this case, PAK1 inhibits one of the GEFs of CDC42 - Neuroepithelial cell transforming 1 ( NET1 ) [9]. Induction of this pathway contributes to PDGF -induced cell migration on collagen and links cell-surface receptors to actin cytoskeletal dynamics and cell motility, which are required for physiological migration and metastatic spread of tumor cells [5].

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. Yokote K, Mori S, Siegbahn A, Ronnstrand L, Wernstedt C, Heldin CH, Claesson-Welsh L
    Structural determinants in the platelet-derived growth factor alpha-receptor implicated in modulation of chemotaxis. The Journal of biological chemistry 1996 Mar 1;271(9):5101-11
  3. Ustach CV, Taube ME, Hurst NJ Jr, Bhagat S, Bonfil RD, Cher ML, Schuger L, Kim HR
    A potential oncogenic activity of platelet-derived growth factor d in prostate cancer progression. Cancer research 2004 Mar 1;64(5):1722-9
  4. Li X, Tjwa M, Moons L, Fons P, Noel A, Ny A, Zhou JM, Lennartsson J, Li H, Luttun A, Ponten A, Devy L, Bouche A, Oh H, Manderveld A, Blacher S, Communi D, Savi P, Bono F, Dewerchin M, Foidart JM, Autiero M, Herbert JM, Collen D, Heldin CH, Eriksson U, Carmeliet P
    Revascularization of ischemic tissues by PDGF-CC via effects on endothelial cells and their progenitors. The Journal of clinical investigation 2005 Jan;115(1):118-27
  5. Jimenez C, Portela RA, Mellado M, Rodriguez-Frade JM, Collard J, Serrano A, Martinez-A C, Avila J, Carrera AC
    Role of the PI3K regulatory subunit in the control of actin organization and cell migration. The Journal of cell biology 2000 Oct 16;151(2):249-62
  6. Pandey A, Podtelejnikov AV, Blagoev B, Bustelo XR, Mann M, Lodish HF
    Analysis of receptor signaling pathways by mass spectrometry: identification of vav-2 as a substrate of the epidermal and platelet-derived growth factor receptors. Proceedings of the National Academy of Sciences of the United States of America 2000 Jan 4;97(1):179-84
  7. Billadeau DD, Mackie SM, Schoon RA, Leibson PJ
    The Rho family guanine nucleotide exchange factor Vav-2 regulates the development of cell-mediated cytotoxicity. The Journal of experimental medicine 2000 Aug 7;192(3):381-92
  8. Buchanan FG, Elliot CM, Gibbs M, Exton JH
    Translocation of the Rac1 guanine nucleotide exchange factor Tiam1 induced by platelet-derived growth factor and lysophosphatidic acid. The Journal of biological chemistry 2000 Mar 31;275(13):9742-8
  9. Shen X, Li J, Hu PP, Waddell D, Zhang J, Wang XF
    The activity of guanine exchange factor NET1 is essential for transforming growth factor-beta-mediated stress fiber formation. The Journal of biological chemistry 2001 May 4;276(18):15362-8