These hormones have a lot of cysteines, and there are over 30 members of this family including: Bone Morphogenetic Proteins, Vg1, Nodal, GDNF (in the news a lot lately), Activin and of course the TGF-Beta #1-5. The latter can turn on cell division or stop cell division.

These hormones are processed so that only the c terminal portion is left, then they dimerized and are secreted from the cell.

The hormones act through transcription factors called Smads.

TGFBeta family members binds to a type II receptor, which allows that receptor to bind to a type I receptor. After dimerization, type II phosphorylates a serine or threonine on the type I receptor. This activates the type I receptor which then phosphorylates different Smad proteins. Smad 4 then binds the phosphorylated Smad and the complex enters the nucleus to act as a transcription factor.

STAT (signal transducers and activators of transcription) proteins are phosphorylated by certain receptor tyrosine kinases including Fibroblast growth factor (FGF) receptor. Also, the JAK tyrosine kinase family can phosphoryate STAT.

Prolactin system: Prl binds receptors that dimerized. JAK is bound to the receptors, and upon their dimerization, the two JAKs can now phosphorylate the receptors at several sites.

The receptors are now activated and they have their own tyrosine kinase activity that hits STAT proteins. Upon this tyrosine phosphorylation , the STATs dimerize and enter the nucleus to act as transcription factors. In this case, the casein gene (milk protein) is turned on.

This is a family of cysteine-rich extracellular glycoproteins. There are at least 15 family members including Wingless (in fruit flies) and Integrated (in vertebrates). Wnt is a combination of these two names. Helps cause muscle cell and kidney (urogenital system) development.

Wnts bind to a receptor called Frizzled; the bound receptor activates Disheveled protein.

Disheveled inhibits an enzyme called glycogen synthase kinase 3 (or GSK3).

When GSK3 is active, it inhibits the dissociation of the beta catenin protein from the APC. APC targets beta catenin for destruction. APC acts as a tumor suppressor: colon cancer arises when the APC is mutated and cannot keep beta catenin from building up.

Thus, Wnt causes increased amounts of beta catenin in the cytoplasm, and the beta catenin enters the nucleus where it binds with LEF (or TCF) to act as a transcription factor to turn on certain genes that cause cell division.

GSK-3 regulates glycogen metabolism also.

Beta catenin is part of the cell adhesion complex—Show figure

Family members:

Sonic hedgehog (shh), desert hedgehog, Indian headgehog

The production of Desert hedgehog is important in the induction of Sertoli cells of the testes. Mice without dhh cannot produce sperm.

Sonic hedgehog is the most famous and is the most widely used family member in the vertebrates. It is named after the Sega Genesis computer character.

Made in the cell, only the amino terminal two thirds is actually secreted. Helps form the nervous system, front-back or side to side axes of the embryo.

The hedgehog protein binds to a receptor named Patched.

Before hedgehog binds patched: while attached to Patched (i.e., no hedgehog around), smoothened is not active. When this occurs, Cubitus interruptus (Ci protein) is bound to microtubules in the cytoplasm through two proteins: Cos2 and Fused protein. When Ci is bound to microtubules, it is cleaved by PKA and Slimb so that part of it enters the nucleus and acts as a negative transcription factor. That is, the Ci protein fragment binds to promoters of genes and turns off these certain genes. Less mRNA, less protein.

When hedgehog binds to patched, patched no longer inhibits smoothened. Smoothened causes the release of Ci protein from microtubules and prevents the cleavage of Ci protein. This involves phosphorylation of Cos2 and Fused and inhibtion of PKA and Slimb.

The intact Ci protein enters the nucleus, binds another protein and acts as an activating transcription factor (turning on the genes the Ci fragment turns off!).

If the patched protein is mutated so that it cannot inhibit smoothened, thus turning on the Shh path, basal cell carcinomas (tumors of the basal cells of the epidermis) arise.

Other mutations that inactivate the Shh path can cause mutations in the developing embryo:

Cyclopia; only one eye in the embryo (also cerebral hemispheres fused, no pituitary gland). Sheep can get this when they eat plants with alkaloids that inhibit cholesterol synthesis. The plants contain jervine and cyclopamine.

Cholesterol is needed for the correct processing of Shh; remember only the first 2/3s of the Shh protein is secreted.

If you artificially mutate the genes for Shh synthesis in mice, reducing Shh synthesis, cyclopia results.

The human form of Ci is called Gli; mutations in the gli gene cause Grieg cephalopolysndactyly (high forehead, extra digits).

So mutations that inhibit or inactivate the Shh path result in malformations, whereas those that activate the Shh path result in cancers.

One cell contains one or more of the following membrane proteins:

Delta,

or Jagged

or Serrate

Any of these proteins will bind to a "receptor" called Notch located on another cell.

Upon binding, the intracellular portion of notch is cut off by a protease. The cleaved portion enters the nucleus, binds to another protein, and acts as a transcription factor. Notch is involved in development of the nervous system (in some cases, tells the cell not to become a neuron) and of the eye.

The extracellular matrix consists of collagen, an adhesive glycoprotein (binds ECM to the cell’s integrin) and proteoglycan complex.

Fibronectin is one type of adhesive glycoprotein that, if it is present in large amounts, can actually tell cells what to do (move, divide). Laminin is another adhesive glycoprotein.

Fibronectin has RGD (three amino acids: arginine, glycine, aspartate) segments that bind to Integrin.

Fibronectin and Integrin require calcium to bind to each other.

Integrin has two subunits and binds, on its intracellular portion, talin, which in turn binds microfilaments.

Thus integrin binds the ECM and intracellular molecules. Somehow, bound integrin can change the expression of genes, leading to, for example, inhibition of cell division.

The latest idea is that the integrins can stimulate a tyrosine kinase-Ras pathway. SEE FIG. 6.37 A.