Signal Transduction Pathways

How do cells communicate (with each other and other aspects of their environment)?

Signal Transduction

• receptor proteins interact w/ ligands (signal molecules) or detect physical changes (light, temp)

• interaction of a receptor w/ a signal results in a series of cellular events

• activation of signal transduction generally leads to differential gene expression (response)

Signal Transduction involving Steroid Hormones: Components

• Signal (steroid hormone): can pass through CM; once bound, anchor is cleaved and receptor + signal enter nucleus

• Receptor (transcription factor): transmembrane or cytoplasmic (for signals that can independently cross CM), held in cytosol by cytoplasmic anchor protein

• Hormone Response Element (cis-acting element)

Steroid Hormones Summary

• Steroid hormone is produced

• steroid hormone crosses CM and binds receptor in the cytosol, releasing the receptor from its cytoplasmic anchor

• hormone/receptor complex acts as a transcription factor; it enters the nucleus and regulates transcription of target genes

Steroid Hormones Example: Glucocorticoids

• GR (glucocorticoid receptor) bound in cytosol by a number of chaperones

• binding of glucocorticoid to its receptor allows it to migrate to the nucleus

• the glucocorticoid/receptor complex binds to its response element (GRE) to regulate transcription (i.e acts as a transcription factor)

• this complex also interacts w/ other transcription factors for complex regulation of gene expression

SIgnal Transduction thru Cell Surface Receptors (e.g. Receptor Tyrosine Kinases)

• signal: can’t pass thru CM

• receptor (transmembrane protein): can bind to signal; exist as monomers on surface, and after binding signal, form dimer

  • dimerization allows for cross-phosphorylation on Tyr residues (cytosol side)

• docking proteins (adaptors): transmit signal from receptor, helps recruit other protein to receptor

  • e.g. GTP binding protein/exchange factors (GTP switch to GDP)

• Guanine nucleotide binding protein (G-protein): GDP inactive, GTP active

  • e.g RAS

• serine/threonine kinases

• transcription factors

Receptor Tyrosine Kinase Signaling Summary

• signal molecule binds to receptor proteins at cell surface, causing receptor to form dimers

• receptor is activated dimerization, and recruits/binds docking/adaptor proteins

• docking protein activate G-protein (by recruiting a protein that helps the G protein exchange GDP for GTP)

• active G protein (e.g. Ras) activates cascade of serine/threonine kinases (e.g. MAP kinases)

• Ser/thr kinases activate transcription factors to regulate changes in gene expression

When signal isn’t its own molecule

• signal can be a ligand on the surface of another cell (signal received from neighboring cell)

Signaling Pathway Example: Erythryopoietin Signaling Pathway

• can signal thru Ras and the MAP kinases

• also signals thru other proteins (e.g. JAK/STAT pathway); more than one pathway occuring

• common element: they regulate transcription factors that control expression of genes involved in cell, function, proliferation, and survival

  • they respond to environmental signals

Why is Ras considered a proto-oncogene?

• the WT form of Ras promotes cell proliferation. If a mutation causes it to be active more than usual, it will become an oncogene and promote excessive cell proliferation (ie. Cancer)

• constantly on → leads to cancer (potential to turn cancerous)

Proto-Oncogene

A gene that promotes cell survival or cell division. It can promote cancer if its expression is dysregulated (ie. Through mutation)

Tumor Suppressor

A gene that prevents cell division, induces cell death, and/or induces DNA repair. A loss of function mutation would promote cancer.