1. Targeting PI3K Signaling as a Therapeutic Approach for Colorectal Cancer 
Jing Zhang, Thomas M. Roberts, Ramesh A. Shivdasani 
Gastroenterology 
Volume 141, Issue 1, Pages (July 2011)
DOI: /j.gastro
Copyright © 2011 AGA Institute Terms and Conditions

2. Figure 1
The class IA PI3K signaling pathway. Growth factor or insulin stimulation activates RTKs. Class IA PI3Ks, including p110α-p85, p110β-p85, and p110δ-p85, are recruited to the plasma membrane by direct interaction with the activated receptors (such as platelet-derived growth factor receptor) or by interaction with adaptor proteins associated with the receptors (such as IRS1). The p110β subunit can also be activated by GPCRs, which are activated by lysophosphatidic acid or chemokines. Activated PI3K converts PIP2 to PIP3, which provides docking sites for signaling proteins such as PDK1 and serine-threonine kinase AKT. Once activated, AKT phosphorylates many downstream effectors to regulate cell processes such as protein synthesis, cell survival, proliferation, and metabolism. PTEN functionally antagonizes PI3K activity by dephosphorylating PIP3.
Gastroenterology  , 50-61DOI: ( /j.gastro )
Copyright © 2011 AGA Institute Terms and Conditions

3. Figure 2
Classification and domain structure of mammalian PI3Ks. PI3Ks are divided into 3 classes (I, II, and III) based on their structural characteristics and substrate preferences. Class IA PI3Ks are heterodimers comprising a p85 regulatory subunit and a p110 catalytic subunit. The p85 subunits share a core structure consisting of a p110-binding domain called the iSH2 domain, flanked by SH2 domains. The longer isoforms, p85α and p85β, also have an SH3 domain and a BCR homology domain (BHD) in their extended N-terminal regions. All class IA p110 subunits have a p85-binding domain at the N-terminus, followed by a Ras-binding domain that interacts with small G-proteins of the RAS family, a putative membrane-binding C2 domain, a helical domain, and a C-terminal catalytic domain. Class IB PI3K is a heterodimer comprising a p101 regulatory subunit and a p110γ catalytic subunit. p110γ is expressed mainly in leukocytes and activated downstream of GPCRs. Class II PI3Ks comprise the monomeric catalytic isoforms PIK3C2α, PIK3C2β, and PIK3C2γ, which have an extended divergent N-terminus followed by a RAS-binding domain, a C2 domain, a helical domain, a catalytic domain, additional Phox homology (PX), and C2 domains at the C-termini. Class III PI3K has a single catalytic member, vacuolar protein-sorting 34 (VPS34).
Gastroenterology  , 50-61DOI: ( /j.gastro )
Copyright © 2011 AGA Institute Terms and Conditions

4. Figure 3
Targeting the PI3K and MEK pathways to treat patients with CRC. (A) The PI3K pathway and MEK pathway, usually considered to act in parallel, are commonly deregulated in colorectal tumors. (B) Possible treatment considerations for patients with colorectal tumors with specific genetic alterations, based on known pathway elements and interactions.
Gastroenterology  , 50-61DOI: ( /j.gastro )
Copyright © 2011 AGA Institute Terms and Conditions