Extra Reading Sharrocks

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Stress-activated kinases

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Inhibit proliferation

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JNK has 10 isoforms as a result of

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Alternative splicing

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JNK binds and phosphorylates p53 leading to

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p53 stabilisation

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JNK activates

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c-Jun

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c-Jun induces the transcription of

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AP-1

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c-Jun can repress

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p53

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p38 induces the transcription of

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IL-1 and TGF-alpha

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p38 is activated by

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cytokines and environmental stress

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JNK is activated by

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DNA damage, decrease in GFs, UV radiation, serum, cytokines

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JNK genes

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1-3

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Most frequent mutations of MAPK in cancer

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Ras and B-Raf

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When ERK is mutated in cancer, genes are amplified e.g.

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AP-1 and c-myc

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Ras and B-raf mutations

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Rarely occur in the same tumour

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Co-expression of Ras and B-Raf leads to

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senescence/lethality

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Ras mutations prevent

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GTP hydrolysis

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Ras associated with the membrane due to

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Isoprenylation at the c-terminus

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Farnesylation inhibitors have been unsuccessful because

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Ras is expressed in all cells

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B-Raf mutations are common in

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Papillary Thyroid and Malignant melanomas

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>90% B-Raf mutations occur at

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V600E

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Ras V600E residue is in the

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activation loop

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In colon at B-Raf mutations often occur along with

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CpG island methylation

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B-raf can heterodimerise with

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Raf-1

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B-raf and Raf-1 heterodimerise when stimulated by

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Mitogens and 14-3-3

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Raf-1 can be suppressed by

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PKA

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Ras mutations uncouple

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PKA and Raf-1

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Mutations rarely occur at

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A-Raf

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Any mutations that occur in A-Raf are

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polymorphisms

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Raf activates

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MEK

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When Raf is the strongest activator?

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B-Raf

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Early gene products of ERK include:

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fos, jun and myc

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sustained ERK signalling promotes

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Cyclin D

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High levels of ERK signalling promotes

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p21

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ERK can promote the transcription of AP-1 by up-regulation of

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Fra-1

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Sorafenib is a non-selective inhibitor of

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Raf

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Raf-chaperone that is the target of inhibition

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HSP90

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Clinical trials target Raf by inhibiting

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MEK1/2

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Difference between c- and v-Jun, v- Jun lacks the...

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delta-domain

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c-Jun delta domain binds to

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JNK and HDAC3

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JNK regulates c-Jun

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transcription

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GSK3 regulates c-Jun

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abundance

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GSK3 phosphorylates c-Jun causing

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Ubiquitination

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High levels of GSK3 usually lead to

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Reduced c-Jun

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The Wnt and P13K both regulate

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GSK3

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Wnt activates dishelleved and Frat leading to inhibition of

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GSK3

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P13K activates

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Akt, leading to inhibition of GSK3

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Gain-of-function mutations in Wnt and P13K lead to

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No degradation of c-Jun

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Before GSK3 can phosphorylate c-Jun

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ERK phosphorylates c-Jun

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v-Jun the Ser423 is mutated so

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ERK does not phosphorylate it

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The best studied immediately early gene is

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Fos

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Modifying chromatin and recruit RNA polII leads to

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Transcription

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Fos is activated by histone (H3S10) acetylation which recruits

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14-3-3 and BRG1

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Contains a constitutively negative charge in the N-region

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B-Raf

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Cancers with high incidence of B-Raf mutations include:

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Papillary thyroid carcinoma and malignant melanoma

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Activating mutations in RET (RTK) are common in

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Papillary thyroid carcinoma

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RTK recruit Grb2 via the

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SH2 domain

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Grb2 recruits Sos via the

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SH3 domain

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Sos activates

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Ras

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PTEN is a

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tumour supressor

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PIP2 -> P1P3 is catalysed by

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P13K

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PIP3 -> PIP2 is catalysed by

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PTEN

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Antisense oligonucleotides are used in treatment to target

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Ras and Raf

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Uses lysine residues to recruit to the membrane (not farnesylation)

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K-Ras