Cell Signaling II

how does the cytoplasmic domain of enzyme couple receptors, such as RTKs, behave

either as an enzyme itself or it will form a complex with another protein that acts like an enzyme

are RAS and PI-3 kinases exclusively activated by RTK

no, not exclusively

they can be activated downstream of other receptors

what does SH2 bind to

the phosphorylated tyrosine residues on RTK

*specific interaction

what does SH3 do

enables protein to act as an adaptor by recruiting SH3 domain-binding proteins to activated RTK, like SOS

how is the RAS protein activated in RTK

• signal molecule binds to RTK, creating a dimer which allows the tyrosines to

• Grb2 (adaptor protein) binds to the phosphorylated tyrosine because it has an SH2 domain

• the Grb2 also has an SH3, who allows SOS that has an SH3 binding domain to bind

• SOS is a Ras GEF which allows for nucleotide exchange

• RAS is now activated since it is bound to GTP

Describe the Gas-Map-kinase signaling pathway

after RAS is activated, MapKKK is activated that activates mapKK that activates mapK that can change gene expression and cell behavior

MAP kinase stands for mitogen active kinase. based on this name, what do you think this stimulates

mitosis!

talk yourself through the western block

remember X is upstream of RAS and Y is downstream

if just X is mutated, signaling is inhibited which is a dominant negative mutations since it stops signaling ; no issue with ERK it just cannot be phosphorylated

RAS is overactive and always on and because X is upstream, it will not affect the overactive RAS because it functions independently

If just Y is mutated, there is no signaling for same reason as just mutant X

If Y is mutant, there will still be no signaling even with overactive RAS because Y is DOWNSTREAM

take away: if RAS functions independently, anything upstream form it isn’t going to do shit, but anything downstream can

Describe RTK and PI3K signaling

• once signaling molecule binds to RTK, dimer forms and autophosphorylates

• P3 kinase is activated and serves as a docking site for intracellular signaling → important for growth

  • PIP(4,5)2 is now PIP(3,4,5)3

what does PIP3 kinase do

take PI(4,5)P2 and add phosphate to the 3rd carbon, making it a PI(3,4,5)P3

*in the photo, without PTEN that is how cancer cells grow

several mutations in KRAS can prevent what

RAS gap activity, making Ras always on