Insulin & RTK Signaling Tournament
Two onboarding diagrams orient you in RTK + insulin signaling. Then eight MCAT-DoK quiz rounds: IRS-1/2 as insulin's unique adaptor, T2DM Ser-phosphorylation insulin resistance, the canonical IR -> IRS -> PI3K -> PIP3 -> Akt -> AS160 -> GLUT4 sequence, the constitutive α2β2 receptor architecture, downstream metabolic effects, RTK vs. TGF-β contrast, and Donohue syndrome.
Where the Signaling by receptor tyrosine kinases fits in Signal Transduction
Receptor tyrosine kinases (RTKs) are the second great cell-surface signaling family - including the insulin receptor, EGFR, FGFR, VEGFR. Insulin uniquely uses IRS-1/2 to amplify PI3K-Akt-mTOR, driving GLUT4, glycogen synthesis, and lipogenesis. Click the highlighted Signaling by receptor tyrosine kinases box to enter the tournament.
Click the highlighted Signaling by receptor tyrosine kinases box to continue.
What this tournament tests
Each task maps to a distinct MCAT cognitive demand. The first two orient you in the broader topology; the next eight test the high-yield mechanism, regulation, sequence and quantitative reasoning that consistently appear on test day.
The Bigger Picture
Anchor RTK signaling inside signal transduction on the live Reactome map.
Whole-Pathway Overview
Pan and zoom the curated WikiPathways insulin signaling figure before you start answering.
Fill in the Blank
Recall IRS-1/2 as insulin's specific adaptor, distinct from Grb2 in most other RTKs.
Disruptor
Predict how chronic mTORC1 / S6K Ser-phosphorylation of IRS-1 drives T2DM insulin resistance.
Sequence Ordering
Trace insulin -> IR -> IRS -> PI3K -> PIP3 -> PDK1 + mTORC2 -> Akt -> AS160 -> GLUT4.
Match the Pairs
Pair each component (IR, IRS, PI3K, Akt, mTORC1, PTEN) with its precise role.
Numeric Input
Recall the constitutive α2β2 (4-subunit) heterotetrameric architecture of the insulin receptor.
Select All That Apply
Identify TRUE downstream metabolic effects (GLUT4, GSK3 inhibition, FOXO exclusion, anti-lipolysis).
Odd One Out
Distinguish TGF-β receptor (Ser/Thr kinase) from RTKs.
Donohue Syndrome Disruptor
Recognize biallelic INSR loss as the molecular extreme of insulin resistance.
Public leaderboard
Your score posts to a global, persistent leaderboard scored by points first, time as tiebreaker.
Insulin / RTK signaling in 60 seconds
RTKs share an architecture: extracellular ligand-binding domain, single transmembrane helix, intracellular tyrosine kinase. Most are monomeric and dimerize on ligand binding; the insulin receptor uniquely is a constitutive α2β2 heterotetramer.
Insulin signaling uses IRS-1/2 as adapters to amplify the PI3K branch: IR -> IRS -> p85/PI3K -> PIP3 -> Akt -> metabolic effects (GLUT4, GSK3 inhibition, FOXO exclusion, mTORC1). The MAPK branch (Grb2-Ras-Raf-MEK-ERK) provides growth signals in parallel.
T2DM is post-receptor: chronic over-nutrition activates mTORC1 + JNK + IKK; these Ser-phosphorylate IRS-1 and target it for degradation. Same insulin binding, no signal output. Receptor itself is INTACT.
PTEN dephosphorylates PIP3 back to PIP2 - it brakes the entire Akt branch. PTEN loss = uncontrolled Akt activity = oncogenic (Cowden syndrome, many sporadic cancers). Donohue / Rabson-Mendenhall = receptor itself is dead = severe neonatal insulin resistance.
FAQ
Why does the insulin receptor not need to dimerize on ligand binding?
It's already a constitutive α2β2 heterotetramer joined by disulfide bonds before insulin arrives. Insulin binding induces a conformational change that brings the two β subunit kinase domains close enough to trans-autophosphorylate. Functionally equivalent to dimerization, structurally pre-formed.
What does Akt actually do downstream?
Akt phosphorylates dozens of substrates: AS160 (releases Rab10 -> GLUT4 vesicle fusion), GSK3 (inhibits it -> glycogen synthase active), FOXO (excludes from nucleus -> stops gluconeogenesis), TSC2 (releases mTORC1), PRAS40, BAD, and many more. It is a master metabolic and pro-survival kinase.
How is rapamycin (sirolimus) related to this pathway?
Rapamycin inhibits mTORC1 specifically (it complexes with FKBP12 and binds mTORC1's FRB domain). It is used as an immunosuppressant and as an anti-restenosis drug on coronary stents. Rapalogs (everolimus) treat some hormone receptor-positive cancers.
Do I need an account to play?
No. The tournament is fully public. You get a randomized handle and your score posts to the public leaderboard at the bottom of this page.
Keep going
The other major branch downstream of RTKs - mitogenic gene expression via Ras-Raf-MEK-ERK.
Different architecture, different second messengers - the GPCR family that opposes insulin's actions.
Overview diagram: Reactome Pathway R-HSA-162582, licensed CC BY 4.0.