| PDGF signals through the phosphatidylinositol and Ras-MAPK cascades
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| Ligation of the PDGF-receptor (PDGF-R) leads to the recruitment and activation of phospholipase C-γ(PLC-γ), which catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) to generate the intracellular second messengers, inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) (see Chapter 38). IP3 stimulates release of Ca2+ from intracellular stores and DAG activates an important signal transducer family, protein kinase C (PKC). Ligation of the PDGF-R also leads to recruitment of another lipid signaling enzyme, phosphoinositide-3-kinase (PI-3-kinase). This enzyme phosphorylates PIP2 yielding the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate (PIP3), which can also activate certain members of the PKC family. In addition, PIP3 can activate another kinase called PIP3-dependent kinase.
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| Thirty percent of all tumors have constitutively active mutants of a signaling element called Ras, which acts as a molecular switch for a key signal transduction pathway in the control of growth and differentiation.
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Figure 41.3 Recruitment and activation of Ras by the PDGF receptor. Ras is anchored in the plasma membrane and recruited to the activated PDGF-R via interaction with the Grb2--Sos complex. Receptor-stimulated GTP/GDP exchange, and hence activation of Ras, is promoted by Sos, whereas GAP inactivates Ras by stimulating its intrinsic GTPase activity. Ras couples the PDGF-R to MAPK activation via stimulation of the intermediary kinases, Raf and MEK kinase. MAPK translocates to the nucleus and phosphorylates (on serine and threonine) key transcription factors involved in the regulation of DNA synthesis and cell division.
MAPK: mitogen-activated protein kinase |
| Rasis a GTPase, which cycles between an inactive Ras-GDP form and an active Ras-GTP form (Fig. 41.3). GTP/GDP
exchange is promoted by a guanine nucleotide exchange factor, called Sos, and the GTPase-activating protein (GAP) inactivates Ras by stimulating its intrinsic GTPase activity (as does the intrinsic GTPase of the α-subunit of heterotrimeric G-proteins; see Chapter 38). Ras is constitutively targeted to the plasma membrane by a post-translational modification involving the addition of a lipophilic farnesyl group (Chapter 16) and is then recruited to the activated PDGF-R by interaction with an adapter protein called Grb2.
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| One of the main effector functions of Ras is to regulate the mitogen-activated protein kinase (MAPK) cascade. MAPK is a serine-threonine kinase that is itself activated by phosphorylation by a dual specificity (tyrosine/threonine) MAPK kinase called MEK. MAPK has two major isoforms, extracellular regulated kinases (ERK) 1 and 2, which translocate to the nucleus and phosphorylate (on serine and threonine) key transcription factors involved in the regulation of DNA synthesis and cell division.
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