23.3
Cascatas de sinalização MAPK
A proteína quinase ativada por mitógeno, ou via MAPK, ativa três quinases sequenciais para regular respostas celulares, como proliferação, diferenciaç…
As vias da proteína quinase ativada por mitógeno ou MAPK retransmitem sinais a jusante dos RTKs para ativar os fatores de transcrição.
Na via de sinalização Ras-MAPK, Raf, a quinase inicial dessa via, liga-se ao dímero da proteína 14-3-3 e permanece inativo no citosol.
A ligação do mitógeno nos RTKs ativa o Ras GTP, que então se liga ao complexo Raf / 14-3-3.
A fosforilação de vários locais em Raf desmonta o complexo, permitindo que Raf dimerize com um monômero fosforilado próximo.
O dimérico Raf agora fosforila e ativa outra quinase, MEK, que por sua vez fosforila a quinase final da cascata, ERK.
O ERK ativado é transportado para o núcleo para fosforilar fatores de transcrição, como c-Jun e c-Fos, e iniciar processos celulares, como proliferação celular, sobrevivência, diferenciação ou apoptose.
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Q1: How does the Ras-MAPK signaling pathway activate downstream kinases?
Mitogen binding activates receptor tyrosine kinases, which stimulate Ras GTP. Activated Ras recruits the Raf/14-3-3 complex to the membrane. Phosphorylation causes the complex to disassemble, allowing Raf to dimerize and phosphorylate MEK, which then activates ERK, the final kinase in the cascade.
Q2: What role do scaffold proteins play in MAPK signaling?
Scaffold proteins like KSR channel signals to the correct MAPK module, ensuring specificity and preventing crosstalk between parallel pathways. They localize kinases and substrates near each other, enhancing signal relay efficiency. This organized positioning allows cells to activate different effector proteins without interference between signaling pathways.
Q3: What are the three main types of MAPK pathways in mammals?
The three MAPK pathway types are ERK, activated by growth factors to promote cell growth and differentiation; JNK, induced by environmental stresses to cause cell death and inflammation; and P38/SAPKs, also stress-activated to promote inflammation, cell death, differentiation, and cell cycle regulation.
Q4: How does activated ERK trigger cellular responses?
Activated ERK translocates to the nucleus where it phosphorylates transcription factors such as c-Jun and c-Fos. These phosphorylated factors trigger gene expression changes, including activation of cyclin D1, which promotes cell cycle progression and initiates cellular processes like proliferation, survival, differentiation, or apoptosis.
Q5: Why is the 14-3-3 protein important in Raf activation?
The 14-3-3 protein dimer binds Raf in the cytosol, keeping it inactive until a signal arrives. Upon mitogen stimulation and Ras activation, the Raf/14-3-3 complex is recruited to the membrane. Phosphorylation at multiple sites causes the complex to disassemble, freeing Raf to dimerize and become catalytically active.
Q6: How do cells prevent crosstalk between different MAPK modules?
Eukaryotes use pathway-specific scaffold proteins that channel incoming signals to the correct MAPK module. These scaffolds localize and orient protein complexes near their substrates, ensuring signal specificity. Although different MAPK pathways often share the same kinases, scaffold proteins direct them to activate different effector proteins without interference.
Q7: What cellular responses result from MAPK pathway activation?
MAPK pathway activation regulates diverse cellular responses including proliferation, differentiation, survival, and apoptosis. ERK pathways promote growth and differentiation; JNK and P38 pathways respond to environmental stresses by triggering inflammation and cell death. The specific response depends on which MAPK module is activated and which transcription factors are phosphorylated.