Quick Reference Guide to Signaling Pathways

This is a fast and dirty outline of what’s going on in a few of the major signaling pathways.

Signaling Pathways Quick Reference:

A. PKA
B. MAPK
C. TGFB/BMP
D. WNT
E. NOTCH
F. HEDGEHOG

Players in PKA
-cAMP
-PKA
-CREB
-CBP

PKA is made up of 4 subunits: 2 regulatory and 2 catalytic. Upon activation from cAMP, PKA catalytic subunits migrate into the nucleus where they phosphorylate CREB, which is a CRE binding protein. CREB with along with co-activator CBP bind to CRE, c-AMP response element in DNA, and stimulate gene transcription.

Players in MAPK
-TKR
-SOS/GBR2
-RAS
-RAF
-MEK
-ERK
-CREB
-CRE

A ligand binds to TKR, tyrosine kinase receptor, on the plasma membrane which becomes phosphorylated. GBR2 binds at the phosphorylation site and activates SOS. SOS acts as a GEF, guanine exchange factor, for RAS, which means it removes GDP from RAS so that RAS can bind to GTP and become activated. Once RAS becomes activated it activates RAF which phosphorylates MEK which phosphorylates ERK. ERK enters the nucleus where it phosphorylates CREB that binds to CRE and stimulates gene transcription

Players in TGFB/BMP
-Receptors type 1 and type 2
-TGFB/BMP ligand
-Smad 2,3
-Smad 1,5,8
-Smad 4

Type 1 and type 2 receptors come together on the plasma membrane. If they bind to a TGFB ligand they phosphorylate and Smad 2/3 become phosphorylated. Smad 4 binds to Smad 2/3 and they become a complex and enter the nucleus and stimulate gene transcription. If type 1/ type 2 receptors bind to a BMP ligand Smad 1/5/8 becomes phosphorylated. This also forms a complex with Smad 4, and the complex moves into the nucleus where it stimulates gene transcription

Players in WNT
-WNT ligand
-Frizzled
-LRP
-Disheveled
-B Catenin
-CK1
-GSK3
-APC
-Axin
-LEF1/TCF
-Groucho

In the absence of WNT signaling (no WNT ligand), B-Catenin is degraded and kept out of the nucleus. It is degraded by becoming phosphorylated for ubiquitylation by CK1 and GSK3. Axin and APC aid in this by serving as scaffolding proteins. When a WNT ligand binds to plasma membrane proteins Frizzled and LRP they recruit the B-Catenin degradation complex to the plasma membrane. Disheveled also becomes phosphorylated by Frizzled as well and is required for signaling, but its role unclear. Axin is phosphorylated and then degraded. This inactivates the degradation complex and B-Catenin accumulates in the cell and migrates to the nucleus. Once in the nucleus B-Catenin binds to LEF1/TCF, displaces the repressor Groucho, and simulates gene transcription.

Players in NOTCH
-Delta
-Notch/NICD
-Gamma secretase
-MAML
-CSL

Notch is a plasma membrane receptors that when it binds to Delta from another cell undergoes cleavage of its cytoplasmic tail. Gamma secretase cleaves the tail of Notch to yeild NICD, Notch Intra Cellular Domain. This then migrates to the nucleus where is forms a complex with CSL and MAML and stimulates gene transcription.

Players in HEDGEHOG
-Hedgehog ligand
-Patched
-Smoothened
-cubus interruptus, Ci
-PKA
-CK1
-Costal2
-Fused

Without hedgehog signaling smoothen is inactivated and Ci, cubus interruptus, is bound in a degradation complex in the cytoplasm with scaffold proteins Costal2 and Fused. Costal2 recruits PKA, GSK3, and CK1 to phosphorylate Ci for degradation. But Ci is not completely destroyed. It is broken up into a smaller protein where is migrates to the nucleus and acts as a transcriptional repressor. Upon hedgehog binding to transmembrane protein Patched, Smoothened becomes phosphorylated by PKA and CK1 and is recruited to the plasma membrane where it recruits Costal2 and Fused. This inhibits Ci degradation and it accumulates and enters the nucleus where it activates the transcription of hedgehog genes.

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