Notch Signaling Tournament
Two onboarding diagrams orient you in Notch signaling. Then eight MCAT-DoK quiz rounds: Delta/Jagged ligands, S2 (ADAM) + S3 (γ-secretase) cleavages, NICD-RBPJ-Mastermind transcription, HES/HEY targets, NOTCH1 mutations in T-ALL, γ-secretase inhibitors, and the Alzheimer's connection.
Where the Signaling by Notch fits in Signal Transduction
Notch is one of the eight major Reactome 'Signal Transduction' branches and the prototype short-range juxtacrine signaling pathway. It uses regulated intramembrane proteolysis - the receptor itself is the messenger after cleavage. Click the highlighted Notch box to enter the tournament.
Click the highlighted Signaling by Notch 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 Notch within the Reactome Signal Transduction overview alongside Wnt and Hedgehog developmental pathways.
Whole-Pathway Overview
Pan and zoom the curated WikiPathways Notch pathway figure before answering questions.
Fill in the Blank
Recall that γ-secretase / presenilin performs the S3 cleavage that releases NICD.
T-ALL Disruptor
Predict why NOTCH1 activating mutations drive T-cell leukemia and how γ-secretase inhibitors target it.
Sequence Ordering
Order ligand binding -> S2 cleavage -> S3 cleavage -> NICD nuclear translocation -> RBPJ activation -> HES/HEY transcription.
Match the Pairs
Pair Delta, Jagged, ADAM10/17, γ-secretase, NICD, RBPJ, Mastermind, and HES/HEY with their precise pathway roles.
Numeric Input
Count the proteolytic cleavages that activate Notch (S1 + S2 + S3).
Select All That Apply
Identify true statements about Notch in T-cell development, intestinal goblet cells, and adult tissue homeostasis.
Odd One Out
Distinguish Notch components from those of the parallel Hedgehog pathway.
γ-secretase / Alzheimer's Disruptor
Predict why γ-secretase inhibitors fail in Alzheimer's despite blocking APP cleavage.
Public leaderboard
Your score posts to a global, persistent leaderboard scored by points first, time as tiebreaker.
Notch signaling in 60 seconds
Notch is unusual: it has no kinase cascade. The receptor itself, after proteolytic processing, is the transcription cofactor. Notch ligands Delta and Jagged are membrane-bound on a neighboring cell (juxtacrine signaling - direct cell-cell contact required).
Endocytosis on the signaling cell mechanically pulls Notch open and exposes the S2 cleavage site, where ADAM10/17 metalloprotease cuts. Then γ-secretase / presenilin performs the S3 cleavage within the membrane, releasing the Notch intracellular domain (NICD).
NICD translocates to the nucleus, binds RBPJ / CSL (converting it from a repressor to an activator), and recruits Mastermind (MAML). Together they activate HES / HEY transcriptional repressors that block tissue-specific differentiation programs.
Pathology: ~50% of T-ALL cases carry activating NOTCH1 mutations. γ-secretase inhibitors are explored in T-ALL but cause severe gut toxicity (intestinal stem cells need Notch). γ-secretase also cleaves APP in Alzheimer's pathology - the basis of failed Aβ-targeting trials.
FAQ
What is 'lateral inhibition'?
A patterning principle where a cell expressing high Delta locks its neighbors into 'low Notch' fates via Notch signaling - and Notch signaling in those neighbors suppresses Delta. The result: salt-and-pepper differentiation (e.g. one cell becomes a neuron while neighbors stay neural progenitors). Lateral inhibition is critical for neural / intestinal lineage patterning.
Why does γ-secretase inhibition cause GI toxicity?
Intestinal stem cells (LGR5+ crypts) require Notch signaling for self-renewal and lineage decisions (Notch promotes absorptive enterocytes; Notch loss promotes secretory goblet cells). γ-secretase inhibitors block Notch in the gut, producing massive goblet cell metaplasia, diarrhea, and weight loss. Substrate-selective γ-secretase modulators are being developed to spare Notch in the gut while still hitting APP for Alzheimer's.
Is γ-secretase the same enzyme that cleaves APP in Alzheimer's?
Yes. γ-secretase (presenilin + nicastrin + APH1 + PEN2) is a single multi-substrate intramembrane protease. It cleaves Notch, APP, ErbB4, CD44, and dozens of other type-I transmembrane proteins. Alzheimer's drugs that broadly inhibit γ-secretase fail because Notch disruption causes severe systemic toxicity - new modulators selectively reduce Aβ42 without abolishing total γ-secretase activity.
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.