A variety of hormonelike polypeptides and proteins. Called growth factors or cytokines, are thought to regulate the growth, differentiation, and proliferation of cells.
Epidermal growth factor (EGF)
A mitogen (a stimulator of cell division) for many kinds of epithelial cells.
Platelet-derived growth factor (PDGF)
Stimulates mitosis in fibroblasts.
Somatomedins (insulinlike growth factors I and II, IGF-1 and IGF-2 in humans)
Mediate actions of growth hormone (GH).
Secreted in the liver (and other tissue cells)
Also regulate the immune system.
Secreted by T cells after they have been activated by binding to a specific antigen-binding cell.
Numerous identical T cells are produced.
Type I protect cells from viral infection by stimulating phosphorylation ins inactivation of a protein factor required for protein synthesis.
Type II (from T lymphocytes) inhibit growth of cancerous cells.
Tumor necrosis factors (TNF) are toxic to tumor cells.
Mechanisms of Hormone Action
Steroid receptors are usually within the cell as the steroid molecules pass through the cell membrane.
Other hormones bind to specific sites on the cell membrane and release within the cell second messengers which actually cause the hormonal response.
This signal transduction also allows for a tremendous amplification of the hormone molecule’s impact on the cell.
Common second messengers are cyclic AMP (cAMP), cGMP, diacylglycerol (DAG), inositol-1,4,5-triphosphate (IP 3 ), and Ca 2+ .
We will examine cAMP synthesis and action in more detail.
cAMP is produced when hormone binds to a membrane receptor. This binding activates a G protein (binds guanine nucleotide) as shown on the next slide.
The stimulated G protein replaces GDP with GTP. This activates the subunit to bind to and activate adenylate cyclase which then produces cAMP.
cAMP then activates a cAMP-dependent protein kinase.
Adenylate cyclase stays activated until the GTP on the subunit of the G protein is hydrolyzed back to GDP.
Thus a single hormone molecule (eg. glucagon) can stimulate synthesis of many cAMP molecules which in turn can turn on phosphorylation and activate, for example, multiple phosphorylase kinase molecules to hydrolyze glycogen to G-1-P.
Adenylate cyclase is deactivated when the subunit of the G protein uses its built in hydrolysis capability to return GTP to GDP.
Before this occurs, however, many protein molecules have been activated. This is the “cascade” process referred to earlier.
From GTP by guanylate cyclase
Two types of guanylate cyclase are involved in signal transduction, one is membrane bound and the other cytoplasmic.
Membrane bound activated by:
Atrial natriuretic factor (ANF) peptide
ANF is released by atrial heart cells responding to increased blood volume.
Lowering blood pressure and diuresis seem to be mediated by cGMP.
Binding of enterotoxin to intestinal cells causes diarrhea via excessive secretion of electrolytes and water into the lumen of the small intestine.
Cytoplasmic guanylate cyclase may bind NO to a heme group to activate the enzyme.
Phosphatidyl Inositol and Ca 2+
The phosphatidyl inositol cycle (slide 36) mediates the action of hormones and growth factors
Phosphatidyl inositol-4,5-bisphosphate (PIP 2 ) is cleaved by phospholipase C to form second messengers DAG and IP 3 (inositol-1,4,5-triphosphate)
DAG activates protein kinase which activates or deactivates an enzyme.
Phosphatidyl Inositol and Ca 2+ -2
IP 3 diffuses to the calcisome (SER) where it binds to a receptor, a calcium channel.
Calcium flows in to the cytoplasm regulating calcium-binding proteins.
Calmodulin mediates many calcium-regulated reactions. It is a regulatory subunit for some enzymes (e. g. phosphorylase kinase important in glycogen metabolism).
Steroid Hormone Mechanism
Signal transduction by hydrophobic hormones (e. g. steroids) result in changes in gene expression.
i. e. protein mix changes in the cell.
Transport into the cell is via binding to a protein.
E. g. : transcortin
sex hormone-binding protein
Steroid Hormone Mechanism-2
In the cell, hormones bind to intracellular receptors. The complex moves to the nucleus. (Slide 39)
In the nucleus, each complex binds to specific DNA segments, called hormone response elements (HRE) , via a zinc finger domain.
The receptor enhances or diminishes transcription of a specific gene.
Each HRE may influence 50-100 genes.
The Insulin Receptor
The insulin receptor (Slide 41) is a trans- membrane glycoprotein with two subunits connected by disulfide bridges.
Insulin binding activates receptor tyrosine kinase activity and causes a phosphorylation cascade that modulates intracellular proteins.
Binding also induces transfer of some proteins to the cell surface.