Stop Overthinking MCAT Signaling Pathways!
Don’t Waste Your Time Figuring Out Pathway Intermediates! ⏱
Don’t worry if you aren’t taking the MCAT, this post is incredibly valuable for you. It will help think of processes and systems within every field — maths, business, law and so on!
The Math
This post has a bit of math — but HEAR ME OUT! You did this math before you had to help “y” find her “x”! So you’ll be completely fine. In fact, let’s just get it out of the way.
You need to know three basic multiplication facts.
(+) × (+) = (+)
(-) × (-) = (+)
(+) × (-) = (-)
That’s all. That wasn’t so hard was it? (See you gotta put your faith in me!)
Knowing this and the steps I'm about to show you will allow you to know the FINAL effect depending on just the initial state (cut out knowing the intermediate steps!).
Let’s take a simple example to set the scene.
Here we have a molecule A, which could be any of the following protein/signaling molecules/hormones etc.
If molecule A is on (high concentration), then the result (R) is on.
If molecule A is off (low concentration), then R is off.
Pretty easy! Right? Let’s move on to 2 molecules (with a twist).
Here we have a molecule A and molecule B. On top of that, we now have “+” or “-” arrows indicating “activation” or “inhibition”, respectively.
Here’s a quick run down.
Scenario 1: A is on —[activates]→ B (turning it on) —[activates]→ Result (R) is on.
Scenario 2: A is on —[activates]→ turning B on —[inhibits]→ Result (R) is off.
Exercise 1: Just go ahead now and mentally check the rest of them.
Okay! So that was 2 molecules. That wasn’t too bad! I mean imagine, you’re literally about to be able to do an 11 step pathway like snap!
The Secret Sauce
Here’s where we bring that multiplication math together. Let’s look at Scenario 2, again.
We know that [Scenario 2: A is on —[activates]→ turning B on —[inhibits]→ Result (R) is off.]. We just did that. Now, how would we do this without explicitly figuring out the state (on or off) of molecule B? That’s the question we care to solve. Here’s how:
Step 1: Determine all the types of regulators (aka “+” arrows or “-” arrows).
Scenario 2: We have a [+ arrow] and a [- arrow].
Step 2: Use your multiplication trick.
Scenario 2: [+ arrow] × [- arrow] = (-) × (+) = (-)
Step 3: Interpret what this means. (’+’ means the same as the initial, while ‘-’ means the opposite of the initial)
Scenario 2: Since I ended with (-) [negative] . That means I must have the opposite of the initial.
Hence, if the question states high or “on” state of molecule A. My result will be “off”.
On the other hand, if the question states low or “off” state of molecule A. My result will be “on”. (This is scenario 4!)
Exercise: Apply it to another scenario you see above.
3 Molecules!
Listen. Everything you just learned it the entire method. However, I want to make sure you are confident with this method. So we’re taking it up a notch. It’s time for 3 molecules!
For this example, we’ll be looking at Scenario 4 (it’s the 4th one).
Scenario 4:
A = on —[+ activates]→ B = on —[- inhibits]→ C = off —[- inhibits]→ D = off.
Great, let’s run it down.Step 1: Determine all the types of regulators (aka “+” arrows or “-” arrows).
Scenario 4: We have a [+ activates], [- inhibits], and then [- inhibits].
Step 2: Use your multiplication trick.
Scenario 4: (+) × (-) × (-) = (+)
Step 3: Interpret what this means. (’+’ means the same as the initial, while ‘-’ means the opposite of the initial)
Scenario 4: Since I have (+) [positive]. That mean I must have the same as the initial.
Hence, if the question states high or “on” state of molecule A. My result will be “on”.
On the other hand, if the question states low or “off” state of molecule A. My result will be “off”.
BEST PART: We never needed to know the intermediate steps!
Great. Just with a bit of math — we can figure out the [end state] of a pathway from the [initial state] of a pathway without explicitly relying on the [intermediate states]!
Try it yourself! (< 3 minutes)
Exercise left to the reader. (let's see if you're paying attention!)
I asked ChatGPT to give me a random string of 11 (not 3) of binary numerals (our favorite 0s and 1s). The 1s represented an [+ activate regulator]; the 0s represented an [- inhibitory regulator].
If molecule A is on (high concentration). What is the result going to be?
If molecule A is off (low concentration). What is the result going to be?
Assume the pathway was a negative feedback loop, where molecule K inhibits molecule A.
If molecule C is ‘off’, how does that affect the molecule K?
What happens to molecule A as a result?
Does this create any downstream effect on molecule C? Explain why or why not.
Assume the pathway actually started from molecule D and ended with molecule K.
If molecule D is on (high concentration). Is molecule K going to upregulated or downregulated?
If molecule D is off (low concentration). Is molecule K going to upregulated or downregulated?
If you got that correct, I just want to let you know there are 2,048 ways that question could’ve gone. There is definitely no 11 step pathway in those MCAT passages. Determine your molecules, write out your arrows (as needed) and then multiply your way to upregulation or downregulation.
Here’s a real MCAT-style question
A newly discovered signaling pathway regulates insulin secretion in pancreatic β-cells. Researchers have determined that:
Glucose activates Protein X.
Protein X activates Enzyme Y.
Enzyme Y inhibits Protein Z.
Protein Z activates Insulin secretion.
A rare mutation results in Enzyme Y being constitutively active.
If glucose levels are high in an individual with this mutation, what will happen to insulin secretion?
A) Insulin secretion will be increased.
B) Insulin secretion will be decreased.
C) Insulin secretion will be unchanged.
D) Insulin secretion will fluctuate unpredictably.
Last Things to Remember
Presence of a Molecule ≠ Activation of that Pathway! Suppose molecule X (an enzyme) inhibits molecule Y. It needs to be in the active state. Therefore, if X is present AND active, then apply the inhibition (-).
The MCAT will use the phrase “constitutively active”, meaning that the baseline activity of this molecule is already on.
Of course, feedback loops exist. What do the loop do? Inhibit? Activate? Then use the appropriate negative or positive to multiply to your result!
Did this give you an "A-ha!" moment? Or did I miss something crucial? Drop your thoughts below!
TL;DR: I gave you the fastest way to determine the results of a pathway without knowing its intermediates. Elementary school mathematics help you figure this out in a snap.