Mitogenic Pathways

The pathways through which extracellular signals are transferred into the follicle cell are conveyed by three membrane-associated transducing systems (Fig. 28-1).

TABLE 28-1. Major Growth Stimulatory and Inhibitory Factors In the Regulation of Thyroid Epithelial Cell Growth

Signaling Pathway Factor

Receptor

Growth Effect

Related Proto-oncogene

AC-cAMP-PKA

Tyrosine kinase receptors

PI turnover-PKC- Ca2t Others

Iodide (via inhibition of cAMP) Epinephrine (inhibition of cAMP) EGF TGF-a FGFs Insulin IGF-I IGF-H HGF

Phorbol esters

TGF-(ii

Iodide

TSH-R

TSH-R

Stimulatory, inhibitory Stimulatory

Stimulatory

Stimulatory Stimulatory Stimulatory

Stimulatory (via IGF-I-R) Stimulatory

Stimulatory (via IGF-I-R)

Stimulatory

Stimulatory

Stimulatory

Stimulatory

Inhibitory

Inhibitory c-erb B (EGF-R)

AC = adenylate cyclase; cAMP = cyclic adenosine monophosphate; PKA = protein kinase A; TSH = thyroid-stimulating hormone; TSH-R = TSH receptor; EGF = epidermal growth factor; EGF-R = EGF receptor; TGF = transforming growth factor; FGF = fibroblast growth factor; FGF-R = FGF receptor; IR = insulin receptor; IGF = insulin-like growth factor; IGF-I-R - 1GF-! receptor; HGF - hepatocyte growth factor; HGF-R - HGF receptor; PDGF * platelet-derived growth factor; PDGF-R = PDGF receptor; PI ™ phosphatidylinosital; PKC = protein kinase C; Ca2* = calcium ion.

1. Activation of the guanosine triphosphate (GTP)-binding protein Gsa in the adenylate cyclase (AC), which evokes the cyclic adenosine monophosphate (cAMP) protein kinase A (PKA) signal (the AC-cAMP-PKA pathway).

2. A cAMP-independent mechanism involving activation of membrane-bound tyrosine kinase receptors (RTKs), resulting in an activation of the ras mitogen-activated protein kinase (MAPK) pathway for transduction of the mitogenic signal.

3. Phospholipid-hydrolyzing mechanisms by which a number of agonists act by interaction with phos-pholipase, which catalyzes the formation of diacyl-glycerol and inositol triphosphate (from membrane phosphatidylinositol [PI] or polyphosphoinositides), resulting in the mobilization of calcium, the activation of protein kinase C, the release of arachidonic acid (precursor for prostaglandins, thromboxanes, and leukotrienes), and the formation of cyclic guanosine monophosphate by activation of guanylate cyclase (the PI-PKC-Ca2+ pathway, or PI cascade).

The TSH receptor confers the physiologic signal from the hypothalamic-pituitary system to the follicle epithelium primarily for regulation of a thyroid hormone secretion rate. The membrane-bound RTK path may confer information from locally produced factors and neighboring cells in paracrine and autocrine loops, whereas agonist interacting with the phospholipid-hydrolyzing system seems to form a more general route for integration of thyroid function and growth with other surveillance systems.

These pathways are usually mitogenic, because activation induces cell replication. It is generally accepted that all pathways are mitogenic. There are, however, distinct species variations, and results from experimental systems cannot be generalized to the human thyroid without careful investigation in well-controlled experimental systems.

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