Pathways

Epidermal growth factor (EGF) binds to the EGF receptor (EGFR), causing EGFR dimerization and transphosphorylation. Phosphorylated EGFR then recruits GRB2, which is bound to the exchange factor SOS. SOS activates RAS by promoting the exchange of GDP for GTP. GTP-bound RAS then activates the RAF-MEK-ERK kinase cascade, driving cell proliferation. RAS is inactivated by its intrinsic GTPase activity, which hydrolyzes GTP back to GDP.

A mutation that impairs the intrinsic GTPase activity of RAS would most likely result in which of the following?

T cell receptor (TCR) activation leads to phosphorylation of the kinase ZAP-70, which phosphorylates the adaptor LAT. LAT recruits PLCg1, which cleaves PIP2 into IP3 and DAG. IP3 triggers calcium release from the endoplasmic reticulum, activating the phosphatase calcineurin. Calcineurin dephosphorylates NFAT, allowing it to translocate to the nucleus and drive cytokine gene expression. 

Treatment with cyclosporin A, a calcineurin inhibitor, would most likely result in which of the following?

The following experimental observations clarify the relationship between PTEN and the development of prostate tumors:

• Wild-type PTEN transcripts are readily detected in noncancerous prostatic epithelium from male PTEN⁺/⁻ mice but are undetectable in cancerous prostatic epithelium from the same mice.
• In male PTEN⁺/⁻ mice, the remaining wild-type PTEN allele undergoes loss of heterozygosity in 100% of cancerous prostatic epithelial cells but in only 12% of noncancerous prostatic epithelial cells.
• Cancerous prostatic epithelium from PTEN⁺/⁻ mice exhibits 9- to 13-fold higher levels of phosphorylated AKT (p-AKT) compared to noncancerous prostatic epithelium from the same mice.
• PTEN dephosphorylates PIP₃, and deletion of PTEN’s phosphatase domain leads to increased AKT phosphorylation in PTEN-expressing cells.
• The growth rate of prostatic tumor cells in culture and their ability to cause death when injected into mice correlate inversely with the level of functional PTEN expression.

Given that the tumorigenicity of a certain mouse prostatic tumor cell line is dependent on AKT-mediated intracellular signaling, mice injected with variants of this cell line that have which of the following modifications would be most likely to survive the longest?

Leptin binds to its receptor (LepR) in hypothalamic neurons, activating the associated kinase JAK2. JAK2 phosphorylates LepR, recruiting STAT3, which JAK2 then phosphorylates. Phosphorylated STAT3 dimerizes, translocates to the nucleus, and increases expression of POMC, which suppresses appetite. SOCS3 is induced by STAT3 and inhibits JAK2 as a negative feedback mechanism.

In a mouse with a loss-of-function mutation in SOCS3 in hypothalamic neurons, which of the following would most likely be observed?

The activity of the non-receptor tyrosine kinase Src is controlled by phosphorylation at two sites. Although Src plays many roles in cells, its canonical function is to regulate Wnt3a.  Phosphorylation of Tyr416 in the activation loop of src stabilizes the active conformation. Phosphorylation of Tyr527 by the kinase CSK promotes an inactive conformation of src in which the phosphorylated tail folds back and occludes the active site. The phosphatase PTP1B removes the inhibitory phosphate from Tyr527.

Treatment of cells with a specific src antagonist would most likely mimic a drug that: