Rab

Kinase cascade

Metabolism raf kinase MAP kinase-kinase MAP kinase p90rsk

Growth figure 19-4 Signal pathway of receptor-activated tyrosine kinase receptors. Activation of receptor-linked tyrosine kinases by cytokines, growth factors, and insulin induces receptor autophosph-orylation. The complex of GRB2 and the son of sevenless (SOS) guanine nucleotide-releasing protein is recruited to the plasma membrane by the receptor via SH2 domain-phosphotyrosine interaction. SOS activates raf kinase, which initiates a phosphorylation cascade, mitogen-activated protein (MAP) kinase-kinase, MAP-kinase, and p90rsk, leading to cellular effects on metabolism and cell growth. Reproduced with permission from Gammeltoft, S., and Kahn, C. R. (1995). Hormone signaling via membrane receptors. In "Endocrinology" (L. J., DeGroot, ed.), 3rd ed., Vol. 1, pp. 17-65. W.B. Saunders Co., Philadelphia, PA.

to involve the growth factor in an heteromeric complex of type I and type II TGF-/3 receptors, which form ligand-receptor complexes of about 65 and 130 kDa, respectively, generating a heterodimer of about 200 kDa. The direct effects of TGF-/3 through its heterodimeric receptor complex appear to be reversible forms of inhibition of cell growth directed at the Gi phase of the cell cycle. TGF-/3 may also interfere with the expression of c-myc, which is a growth factor for many cells. Also, TGF-/3 may affect c-myc expression together with pRB, the protein product of the retinoblastoma gene. The stimulatory effects of this growth factor are more indirect than the negative effects and may be accounted for by the ability of TGF-/3 to induce other growth factors, for example, the /3-chain of PDGF. In some cases, TGF-/8 has been shown to be a signal for inducing apoptosis. Although this mechanism is not well understood, it is becoming clear that cascades of cysteine proteases are involved in apoptosis, and these proteases, once activated, catalyze the cleavage of important proteins in the cell and may also account for the activation of other destructive enzymes, such as nucleases. Which particular proteases are activated by TGF-/3 will prove to be of interest.

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Supplements For Diabetics

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