Non-Receptor Tyrosine Kinases & The JAK-STAT Pathway!!

Written By Vaishnavi Kolluru

A kinase is an enzyme that attaches a phosphate group to another molecule. They are usually named after the thing that they phosphorylate. For example, creatine kinase phosphorylates creatine.

Kinases add phosphate groups to the hydroxyl group of a molecule to aid in the dehydration synthesis reaction. Here's what that looks like:

When phosphorylating proteins, there are three options for amino acids to phosphorylate on the side chain: only tyrosine (Y), serine (S), and threonine (T) have -OH groups on their R groups. (We cannot usually attach phosphate groups to the OH of the carboxyl group, which every amino acid has, since those are usually connected to the subsequent amino acid's amino group residue.) 

There are thus three important classes of kinases: serine/threonine kinases (phosphorylate on a serine/threonine residue), receptor tyrosine kinases, and non-receptor tyrosine kinases.

The first two categories of kinases are usually covered in introductory biology textbooks, so I won’t go over them (I can’t outdo a nice concise Campbell’s figure LOL). It’s just important to keep in mind where each kind of kinase can be found in the body. Here’s a gorgeous figure from Medicosis Perfectionalis summarizing cell signaling pathway locations:

Note: I’ve linked the videos about S/T kinases and RTKs from Medicosis at the end of the article, so if you want to learn more about those, please check out the videos!

Let’s move on to how non-receptor tyrosine kinases work. When a ligand binds, these membrane-embedded dimers recruit intracellular JAK proteins. (Fun fact: JAK used to mean “Just Another Kinase” before people realized JAKs actually play an integral role in cell signaling. Now, scientists call them “Janus Kinases” in shame.) Once JAKs phosphorylate + activate each other, they phosphorylate the tyrosines attached to the receptor, as shown below.

Phosphorylated tyrosines attract signal transducer and activators of transcription (STAT) proteins. STAT proteins have a Src homology 2 (SH2) domains which allow docking to the phosphorylated tyrosine residues. Upon STAT attachment, the JAKs phosphorylate the STATs, so the STATs dimerize and act as transcription factors. The region of DNA promoters that STAT dimers bind to are called cytokine-responsive elements (CREs). Different JAK-STAT combinations target different CREs. 

Among other products, CREs often promote production of cyclins. This is pertinent to cancer treatment approaches; overactivation of the JAK-STAT signaling pathway (whether through too much cytokine, too much STAT protein, or inappropriate phosphorylation/recruitment of STAT) increases production of cyclins, which activate cyclin-dependent kinases, which promote progression of the cell cycle. Thus, one avenue by which researchers are approaching cancer treatment on the molecular level is by examining regulation of the JAK-STAT pathway.

So, yeah. That’s NRTKs for ya. Thanks for reading!!

Also, please don’t hesitate to dm me (humble hornworth #7404) on Discord if you have any article topic suggestions! I’m kinda in a dry spell lol, because I’m just doing review for ARBC and not learning any new material yet. 

That said, here are some gorgeous videos about this topic:

<3

Vaishnavi Kolluru
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