tyrosine kinase-assocaited signaling pathways

What is the general function of Epidermal Growth Factor (EGF) when it binds to its RTK receptors?

It stimulates cell survival, growth, proliferation, or differentiation of various cell types and acts as an inductive signal in development.

Which signal protein stimulates carbohydrate utilization and protein synthesis via the insulin receptor?

Insulin.

Nerve growth factor (NGF) binds to the Trk A receptor to stimulate what response?

It stimulates the survival and growth of some neurons.

What is the primary function of Macrophage-colony-stimulating factor (MCSF)?

It stimulates monocyte/macrophage proliferation and differentiation.

What dual role do Fibroblast growth factors (FGF1 to FGF24) play in cellular processes?

They stimulate proliferation of various cell types and inhibit differentiation of some precursor cells.

Vascular endothelial growth factor (VEGF) binds to VEGF receptors to stimulate which process?

Angiogenesis (the formation of new blood vessels).

What are the two primary functions of Ephrins (A and B types)?

They stimulate angiogenesis and guide cell and axon migration.

The transmembrane segment of a typical RTK consists of 20-25 hydrophobic amino acids in what secondary structure?

An alpha-helical structure.

In the activation of RTKs, what is the initial event that occurs upon ligand binding?

The ligand induces dimerization of the receptor monomers.

After RTK dimerization, the kinase domain of one subunit phosphorylates the other subunit on specific tyrosine residues. What is this process called?

Cross-phosphorylation or trans-autophosphorylation.

What is the function of the newly formed phospho-tyrosine residues on an activated RTK's intracellular domain?

They act as high-affinity binding sites (docking sites) for specific intracellular signaling proteins.

In the PDGF receptor signaling pathway, what domain on the adaptor protein Grb2 recognizes and binds to the phospho-tyrosine residues?

The SH2 domain.

The SH3 domains of the Grb2 adaptor protein bind to proline-rich regions on which specific protein?

Sos, a guanine nucleotide exchange factor (GEF).

What is the function of Sos after it is recruited to the plasma membrane by Grb2?

It acts as a GEF to swap GDP for GTP on Ras, thereby activating it.

Once activated, Ras-GTP binds to the inhibitory domain of which serine/threonine kinase, leading to its activation?

Raf.

In the Ras/Raf pathway, Raf activates , which in turn activates .

MEK; ERK

After being activated in the cytoplasm, where does phosphorylated ERK (pERK) translocate to exert its function?

It translocates to the nucleus.

What is the ultimate function of pERK once it enters the nucleus?

It interacts with transcription factors (Tis) to trigger gene expression.

How does ERK contribute to the negative feedback regulation of the Ras pathway?

Active ERK phosphorylates Sos, preventing it from binding to Grb2 and thus inhibiting further Ras activation.

What is the function of MKP (MAP Kinase Phosphatase) in regulating the Ras/Raf/MEK/ERK pathway?

MKP removes the activating phosphate groups from ERK, causing its dephosphorylation and turning the pathway off.

What protein is recruited by the activated PDGF receptor to accelerate the inactivation of Ras?

RasGAP (GTPase-activating protein).

How does RasGAP inactivate Ras?

It accelerates the intrinsic GTPase activity of Ras, which hydrolyzes GTP to GDP.

What protein is recruited by the activated PDGFR to trigger endocytic internalization and permanent signal termination?

Cbl.

Besides receptor internalization, what is another mechanism for signal termination where phosphatases like Shp1/2 are recruited to the receptor?

Receptor dephosphorylation, where the phosphatases remove the activating phosphates from the receptor's tyrosine residues.

What is the main function of the Rho family of small GTPases (e.g., Rho, Rac, Cdc42)?

They relay signals from surface receptors to the cytoskeleton and elsewhere.

The Ran family of monomeric GTPases is involved in regulating which two key cellular processes?

Mitotic spindle assembly and the nuclear transport of RNAs and proteins.

What function is associated with the Rab family (Rab1-60) of monomeric GTPases?

They regulate intracellular vesicle traffic.

What percentage of cutaneous melanomas have an activated Ras/Raf/MEK/ERK pathway?

80%.

In melanoma, a common mutation in the BRAF gene, the V600 mutation, results in what change to the BRAF kinase?

It becomes a constitutively active molecule with increased kinase activity.

What is the primary challenge observed after initial successful treatment of malignant melanoma with BRAF kinase inhibitors?

The rapid development of resistance, leading to disease relapse and progression.

To combat resistance, patients with BRAF-mutant melanoma are often treated with a combination of a BRAF inhibitor and an inhibitor of which other kinase in the pathway?

A MEK inhibitor (e.g., trametinib).

Vemurafenib and dabrafenib are therapeutic agents designed to inhibit which specific protein?

Mutant BRAF.

How do single-pass transmembrane receptors like cytokine receptors differ from RTKs regarding kinase activity?

They have no intrinsic kinase activity and rely on separate, non-covalently attached kinases (receptor-associated tyrosine kinases).

Receptors for interferons and interleukins are associated with which family of tyrosine kinases?

The Janus Kinase (JAK) family.

In the JAK/STAT pathway, what event brings the associated JAKs close enough to cross-phosphorylate each other?

The binding of a ligand (cytokine), which causes the receptor monomers to dimerize.

The phosphorylated tyrosine residues on an activated JAK/receptor complex serve as docking sites for what proteins?

STAT (Signal Transducers and Activators of Transcription) proteins.

After binding to the receptor complex, STAT proteins are phosphorylated by _, causing them to dimerize and translocate to the nucleus.

JAKs

What is the function of the STAT dimer once it enters the nucleus?

It binds to DNA to regulate gene transcription.

What family of proteins provides negative feedback in the JAK/STAT pathway by inhibiting JAK kinase activity and targeting components for degradation?

SOCS (Suppressors of Cytokine Signaling).

How do SOCS proteins lead to the degradation of the receptor and JAKs?

They target them for ubiquitination, which tags them for degradation by the proteasome.

What is the role of PTPs (protein tyrosine phosphatases) in regulating the JAK/STAT pathway?

They remove the activating phosphate groups from both JAKs and STATs.

How do PIAS (protein inhibitors of activated STAT) proteins regulate the JAK/STAT pathway within the nucleus?

They physically block the DNA-binding domain of the activated STAT dimer or interfere with its transcriptional activity.

T-cell receptors (TCRs) are associated with which two receptor-associated tyrosine kinases mentioned in the text?

LCK and ZAP70.

In TCR signaling, antigen binding leads to receptor clustering, which allows LCK to phosphorylate what component of the complex?

The intracellular TCR zeta-chain.

The phosphorylation of the TCR $\zeta$-chain by LCK leads to the recruitment of which other kinase?

ZAP70.

Integrins, which link the cell's cytoskeleton to the extracellular matrix, are associated with which kinases?

SFK (Src family kinases) and FAK (Focal Adhesion Kinase).

Ligand binding to integrins causes their aggregation, leading to the activation of which kinase?

FAK (Focal Adhesion Kinase).

Hematopoiesis, the production of blood cells, is driven by the proliferation and differentiation of what initial cell type?

Multilineage stem cells (HSCs - Hematopoietic Stem Cells).

According to the diagram, what cytokine maintains the self-renewal of Hematopoietic Stem Cells (HSCs)?

Thrombopoietin (Tpo).

The differentiation of a Common Myeloid Progenitor (CMP) into a Megakaryocyte-Erythroid Progenitor (MEP) is driven by which cytokines?

IL-3, Tpo, and SCF.

Which cytokine specifically drives the differentiation of MEPs into erythroid progenitors (CFU-E)?

Erythropoietin (Epo).

Which cytokine specifically drives the differentiation of MEPs into megakaryocytes (MK)?

Thrombopoietin (Tpo).

The Common Myeloid Progenitor (CMP) can differentiate into a Granulocyte-Macrophage progenitor (GM) under the influence of what cytokine?

GM-CSF (Granulocyte-macrophage colony-stimulating factor).

Megakaryocytes (MK) are the precursors to what component of blood?

Platelets.

Both the Tpo and Epo receptors signal through which specific Janus Kinase?

JAK2.

Signaling via JAK2 from the Tpo and Epo receptors activates which specific STAT proteins?

STAT3, STAT5a, and STAT5b.

Overactivation of the JAK2-STAT pathway can lead to what type of disease?

Blood cell cancer (myeloproliferative neoplasms).

The V617F mutation, which contributes to myeloproliferative neoplasms, occurs in which specific protein?

JAK2.

According to the activity graph, how does the specific activity of the JAK2 V678F mutant compare to the wild-type (wt) protein?

The V678F mutant has a significantly higher specific activity (disease level, 8%) compared to the normal wild-type (1%).

What is the mechanism of action for the drug Ruxolitinib?

It is a JAK1/2 inhibitor.

For which two conditions is the JAK inhibitor Ruxolitinib licensed as a therapeutic agent?

Myelofibrosis and polycythemia vera.