Block3 2.single Pass Receptor Signaling

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3 main types of single pass receptors: Cytokine receptors, RTK's, and TGF-beta

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1. Cytokine receptors. Extrinsic kinase; the kinase is NOT part of the receptor itself. Ex. Jak/Stat
2. RTK's intrinsic kinase
3. TGF-beta intrinsic kinase
The ultimate effect is on gene expression almost every time, and the receptors dimerize every time in response to ligand binding. The internal parts of the receptors become pho and serve as docking sites for other protein complexes. Also all seem to contain transmembrane regions made up of alpha helices.

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Cytokine Receptors and JAK/STAT Pathway (erythropoetin)

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Jak is an extrinsic kinase associated with the receptor. It has a lip domain that normally keeps it inactive, but the dimerization of the receptors causes lip domain to get pho and then Jak pho Tyr residues on receptor. These serve as a scaffolding for complexes to dock.

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Docking Sites for Protein:Protein Interaction: PTB and SH2

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PTB and SH2 = proteins that like to interact with p-Tyr. They then may serve as docking sites or pho other proteins.

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STAT

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STAT gets pho when it gets close to JAK. It then dimerizes with another phospho-STAT. This dimer goes into nucleus and binds DNA, influencing gene expression.

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3 Examples of Cytokine Signaling

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1. Hematopoietic RBC differentiation - Erythropoietin (JAK/STAT)
2. Prolactin signaling → mammary gland milk production.
3. Interferon response: proteins made and released by host cells in response to the presence of pathogens such as viruses, bacteria, parasites or tumor cells. They allow for communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors

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Receptor Tyrosine Kinases

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Basically the same mechanisms of function as cytokine receptors except the kinase is part of the receptor itself. Dimerization causes phospo of the tyrosine kinases, these autopho other parts of receptors.

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RTK Activation of Ras: EGF and the EGF receptor

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Ras is sitting there near RTK bound with GDP. EGFR's bind EGF, dimerization. 
GRB2 binds to p-Tyr (through an SH2 domain), then binds up Sos. 
Sos causes the exchange of GDP for GTP in Ras. 
This can now send signals into the cell via the MAPK pathway. NOTE Ras is a monomeric G-protein, not trimeric!

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The Ras-MAPK Pathway (think pERK)

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Common pathway, know it:
Ras ->
Raf (MAPKKK, Ser/Thr) ->
MEK (MAPKK, Tyr, Ser/Thr) ->
ERK (MAPK, Ser/Thr)

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3 Examples of RTK Signaling

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Growth is the underlying theme.
1. Epidermal growth factor receptor: development of multile tissues, deregulated in cancer Ex. a constitutively active Ras = uncontrolled growth, or receptors that dimerize on their own without the ligand = uncontrolled growth. Ras/MAPK is the most common pathway
2. Vascular Endothelial Growth Factor Receptor (VEGFR). Cancers must get have blood supply, so VegF is very important
3. Insulin receptor (not always about growth). Glucose homeostasis, inactivated in some forms of diabetes.

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Ligand EGF Promotes HER Dimerization

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HER = human epidermal growth factor receptor.
HER2/Neu mutation is one that converts it into constitutively active form, associated with breast cancer. Amplification or over-expression of this gene has been shown to play an important role in the pathogenesis and progression of certain aggressive types of breast cancer and in recent years it has evolved to become an important biomarker and target of therapy for the disease.

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TGFb/Smad Signaling Pathway

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R1, R2, R3 subunits. Either
R2 or R3 can bind ligand
 (TGF beta). Once R1 joins the complex, it gets phospho by R2/3. It is a kinase also, it phosphorylates Smad3, changing its conformation. It has a NLS on it that is now exposed. Smad4 interacts with two Smad3's (one phospho, one isn't???), making a crazy structure that gets into nucleus and mediates transcription.

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Examples of TGFb Signaling: In this case anti-cancer.

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1. Secretion of extracellular matrix proteins in epithelial cells and fibroblasts, AND proteins (PAI1) that inhibit serum proteases that degrade such matrix proteins. More PAI1 (plasminogen activator inhibitor 1) will PREVENT a cancer from metastasizing because it helps maintain the ECM, which does not allow cancer to spread.
2. TGF-beta signaling prevents growth by inducing CDKI p15 and PAI1. p15 is a cell cycle breaker, prevents proliferation. PAI1 is also preventing growth. Unfortunately, several cancers have something mutated (for example, Smad is mutated and the induction of these anti-metastasis molecules is destroyed) and the TGFbeta anti-growth effects don't work. Happens through Smads or receptors themselves.

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CLINICAL: Multiple sclerosis - an autoimmune disease. Treatment with Interferon therapy (Cytokine receptor, JAK/STAT

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Our WBC's are attacking myelin sheaths associated with nerve cells. MS plaques form. Message traveling through axons goes very slowly because of the destruction of the myelin. Treatment:
1.Suppress Pro-Inflammatory Cytokines:
IL1-α, IL1-β, IL6, TNF-α, LIF, IFN-γ, etc…
2. Expression Anti-Inflammatory Cytokines:
IL4, IL10, IL13, IL16, IFN-α, TGF-β, etc…