Receptor Tyrosine Kinases

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How are RTKs generally activated?

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Extracellular portion binds ligands; causes a dimerization of receptors.

Dimerization causes the activation of the cytoplasmic kinase domain. Once activated, it does through trans-autophosphorylation (see notes) which activates the RTK

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What are adapter proteins? ?

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Adapter proteins contain unique domains that recognize specific sequences on RTKs

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What are the two main domains on adapter proteins?

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SH2 (src homology 2 domain) and PTB (phosphotyrosine-binding domain)

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SH2 domain

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src homology 2 domain. Recognizes phosphorylated tyrosine residues. Found on GRB (growth factor receptor bound protein)

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PTB domain

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phosphotyrosine-binding domain. Found on multi-docking proteins, serve as docking sites for other signal transduction proteins. Brings other adapter proteins in.

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Ras protein

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Monomeric G protein. Has GTPase function. Downstream effector of RTK signaling.

Regulated from GEFs and GAPs

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Epidermal growth factor (EGF)

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Binds receptor EGFR; promotes dimerization and the activation of the cytosolic kinase domain. Causes autophosphorylation of EGFR

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Epidermal growth factor receptor (EGFR)

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Binds to EGF and dimerizes. Causes activation of the cytosolic kinase domain and autophosphorylation

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SH3 domain

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Facilitates protein-protein interactions. Found on GRB (growth factor receptor bound protein). Binds to proline residues on Sos

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Growth factor receptor bound protein (GRB)

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Contains one SH2 and two SH3 domains, that recognize and bind to phosphorylated tyrosine residues on EGFR.

Adapter protein with NO ENZYMATIC ACTIVITY

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Sos protein

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A GEF. SH3 binds to the proline residues on it. Activated Sos leads to recruitment of Ras.

Promotes dissociation of GDP from Ras

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Ras protein

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Recruited by activated Sos. Once activated by binding GTP, dissociates from Sos.

Active Ras triggers the downstream kinase cascase (Raf--> MEK -->MAPKKK --> MAPKK --> MAPK)

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Raf protein/MAPKKK

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Activated by the hydrolysis of GTP on Ras. Usually bound to inhibitory protein 14-3-3. Phosphorylates/activates MEK.

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14-3-3 protein

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Inhibitor of Raf

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MEK/MAPKK

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Activated by Raf, phosphorylates/activates MAPK

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MAPK

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Mitogen-activated protein kinase.

Regulates many parts of the cell cycle.

Phosphorylates CDK

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Her2 Receptor

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Example of an EGF. When mutated, causes artificial dimerization and activated of receptor in absence of ligand (Neu)

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ErbB oncoprotein

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Deletion in this causes loss of extracellular ligand bind domain in another EGF receptor leads to constitutive activation of cytoplasmic kinase domain. Leads to it always being turned on (ayy)

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HER1-HER4

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Bind epidermal growth factors in humans.

HER1 makes homodimers.

HER2 cannot directly bind a ligand; instead forms heterodimers with HER1,3 or 4 that leads to activation

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What's the importance of HER2 in breast cancer?

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25% of breast cancers have a huge amplification of HER2. This changes the dynamics of the cell and leads to HER2 being turned on inappropriately

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Herceptin

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A drug that targets HER2; antibody-based approach