Lecture 10- TGFbeta and FGF signaling

Cells need to communicate with each other during development to instruct a signal to change their behaviour. Change in behaviour often leads to changes in cell fate

• Reception: the ligand (growth factor, signalling molecule) binds to a cell surface receptor and activates it • Transduction: receptor activation induces the transduction of the signal from the membrane to the nucleus via a cascade of secondary messenger activation in the cytoplasm • Response: a transcription factor is activated and induces the transcription of specific target genes within the nucleus

• BMP-like family • GDNFs family • TGF-beta like family

BMPs, GDFs and AMH • Role in bone formation • BMPs are important in embryonic development

BMP2/4 are involved in he specification of the limb and patterning of the mesoderm

GDNF, Artemin, Neuturin and Perserin

TGF-beta, Activins and Nodal • TGF-beta: important in controlling the formation of the ECM and in cell division • Activin/Nodal: role in differentiation of the mesoderm, the determination of the A/P axis and the establishment of asymmetry

• TGF-β ligand binds to TGF-βR2 on the cell membrane • This triggers the dimerization of TGF-βR2 to TGF-βR1 • When the two receptors become close to each other, TGF-βR2 phosphorylates TGF-βR1 • This phosphorylation activates the receptor • Activation of the receptor leads to the phosphorylation of an intracellular SMAD complex • This regulatory SMAD complex enter the nucleus and can either activate or repress target genes and lead to TGF-β-induced cell responses

• BMP dimer binds to a receptor molecule in the cell membrane • The ligand binding to the receptor causes subunit II to phosphorylate receptor subunit 1 • Receptor subunit 1 then phosphorylates intracellular Smad1/5 protein • The phosphorylated Smad protein binds to Smad4 to form a transcriptional regulatory complex • The regulatory complex enters the nucleus and then either activates or represses target genes. Sometimes transcriptional cofactors are also involved

Non-conical pathways

• Noggin 2. Chordin

• The antagonists act by binding to the ligand and preventing the BMP from binding to its receptor • The inhibitors are present at various very restricted places in specific groups of cells in specific tissues • Through their diffusion, they control the level of response to BMP signalling that occurs within cells • They play an important role in fine tuning the level of response to BMP signalling that occurs within a cell which is essential in cell fate choice and cell fate specification

Involved in the shaping and dorsalising of the mesoderm

Injected mRNA into artificially ventralised frog embryos and looked at the ability of mRNA to rescue the dorsal structures normally present

Are transmembrane receptor where binding of an extracellular ligand (often growth factors) causes enzymatic activity on the intracellular side

Roles in the ways cells proliferate, differentiate and move inside the animal tissues

Because intracellularly secondary messengers are numerous and this class of proteins tend to activate numerous second messengers via a cascade

Enzyme linked receptors within extracellular environments as they are not diffusable

RTKs

• 20 families of RTKs * 58 RTK genes identified in the human genomes

• Mostly monomers • Extracellular domains vary greatly however there are a few units conserved and repeated (ligand binding activity) • Intracellular domains are highly conserved and have a catalytic domain which carries kinase activity (enzyme-linked receptors) • Single transmembrane domain also conserved (25-38 AA)

Insulin receptor

• Activation occurs when the ligand binds to the extracellular ligand binding domain of 2 inactive RTK • Causes a dimer to form from 2 monomers and they are brought closer together • The change in conformation activates the intracellular tyrosine kinase domain • Once positioned correctly, the kinase domains phosphorylate each other (cross-phosphorylation) • This increases the activity of the kinase, stabilises the receptor in the active state, causes the kinase to phosphorylate other tyrosine residues in the receptor to create Sh2 domain docking sites for intracellular molecules • The docking sites created in the different receptors will be specific for the intracellular substrates and ultimately leads to the diverse responses in RTKs

The formation of a dimer from 2 monomers