Page 23 - Read Online
P. 23
of two RET proteins on lipid rafts. [109] Like other receptor of proteins that regulate several processes related with
tyrosine kinases, RET can activate various signaling cell survival. [114,119] First, AKT has anti-apoptotic effects
pathways including ERK, PI3K/AKT, the p38 mitogen through the phosphorylation and inhibition of pro-
activated protein kinase and the c-Jun N-terminal kinase apoptotic proteins, such as BAD, MDM2 and members of
(JNK) pathways. [109,110] AKT is constitutively expressed the FOX family. Second, AKT promotes the progression
in GBM cells and its activation induces uncontrolled of the cell cycle by blocking the degradation of cyclin D
growth, resistance to apoptosis, and enhanced tumor and inactivating the inhibitors of the cell cycle p21 and
invasiveness, [111] by inactivating pro-apoptotic proteins p27. Finally, AKT activates the mammalian target of
as BAD and procaspase-9 [Figure 1], as well as the rapamycin (mTOR) kinase by inhibiting a complex formed
transcription factor forkhead box O (FOXO). [111] Thus, the by the tumor suppressor proteins tuberous sclerosis 1
inhibition of AKT is an important therapeutic target for the and 2. In turn mTOR increases protein synthesis and cell
treatment of gliomas. The activation of AKT is regulated proliferation. [114,119]
by PI3K, a member of the intracellular lipid kinase family,
which catalyzes the generation of phosphatidylinositol- Additionality, we found that Gas1 inhibits cell growth
3,4,5-triphosphate (PIP3) from phosphatidylinositol-4,5- through a RET-independent mechanism. Gas1 decreases
triphosphate (PIP2). [112] PIP3 recruits AKT to the plasma the viability of MDA-MB-231 human breast cancer
membrane where it is phosphorylated in Thr308 by cells, interfering with the interaction between ARTN
phosphoinositide dependent kinase 1 and in Ser473 by and GFRα3, leading to a decrement of the activation of
PDK2, which results in the full activation of AKT. [113] On ERK1/2. [120] In turn, the activation of the ERK pathway
the other hand, the activation of the PI3K/AKT signaling is triggered by a wide variety of receptor tyrosine kinases
pathway is reduced when PIP3 is dephosphorylated activated by growth factors and cytokines. ERK1/2 is
and converted to PIP2 by the activity of PTEN. [114] In
neuroblastoma and glioma cells, Gas1 blocks cell cycle activated by the small G protein Ras-Raf family members
progression, inhibits proliferation and induces cell death by (Raf-1, A-Raf, B-Raf) followed by MEK1/2. ERK1/2
inhibiting the GDNF/AKT pathway. [107,108,115,116] We showed controls either cell survival or apoptosis by regulating the
that Gas1 prevents the phosphorylation of Ret Tyr1062 and activity of anti- and pro-apoptotic transcription factors. [121]
reduces the activation of AKT [Figure 1]. This leads to the The phosphorylations of ERK 1/2 promote cell survival
translocation of BAD to the mitochondria and the release by enhancing the transcription and activity of the anti-
of cytochrome-C to the cytosol which in turn induces apoptotic molecules Bcl-2, myeloid cell leukemia 1 and
the activation of Caspases 9 and 3. [107,108,115-118] Recently B-cell lymphoma-extra large. [122] Alternatively, ERK1/2
Wang and et al. [100] demonstrated that Gas1 promotes downregulate the expression and inhibit the activity
excitotoxicity in dopaminergic neurons by inhibiting the of the pro-apoptotic protein Bcl2-interacting mediator.
GDNF signaling pathway. Moreover, under conditions of oxidative stress, ERK has
pro-apoptotic effects; [123] however this process it is not well
AKT phosphorylates, activates, or inhibits a number understood yet.
Figure 2: Pathways activated in gliomas and corresponding targets of Gas1
106
Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ March 11, 2016 ¦