Kinetics of receptor tyrosine kinase activation define ERK signaling dynamics.
Kinetics of receptor tyrosine kinase activation define ERK signaling dynamics.
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DOI：
10.1126/scisignal.aaz5267
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发表时间：
2020-08-18
影响因子：
7.3
通讯作者：
Lemmon MA
中科院分区：
文献类型：
--
作者：
Kiyatkin A;van Alderwerelt van Rosenburgh IK;Klein DE;Lemmon MA
在响应于受体酪氨酸激酶（RTK）的激活时，关键的细胞命运决定取决于ERK信号传导的持续时间和动力学。在PC 12细胞中，表皮生长因子（EGF）诱导导致细胞增殖的瞬时ERK活化，而神经生长因子（NGF）促进持续的ERK活化和细胞分化。这些差异通常被认为反映了Raf-MEK-ERK信号网络中不同的反馈机制，受体本身充当简单的上游输入。我们未能证实预期的差异反馈类型时，调查瞬时与持续的信号下游的EGF受体（EGFR）和NGF受体（TrkA）。相反，我们发现，ERK信号忠实地遵循RTK动态时，受体信号以不同的方式调制。当受体内化被药物或突变抑制时，或在嵌合受体中可能具有受损的二聚化时，EGFR活化从瞬时转变为持续，随后是ERK活化动力学。加入亚化学计量水平的EGFR抑制剂厄洛替尼以减少激酶活化寿命后，EGFR信号传导也变得更加持续。同样，ERK信号传导动力学遵循受体活化动力学。我们的研究结果表明，RTK激活动力学在确定MAP激酶级联信号动力学和细胞命运决定中起着至关重要的作用，并且可以通过以不同的方式激活给定的RTK来选择信号结果。
In responses to activation of receptor tyrosine kinases (RTKs), crucial cell fate decisions depend on the duration and dynamics of ERK signaling. In PC12 cells, epidermal growth factor (EGF) induces transient ERK activation that leads to cell proliferation, whereas nerve growth factor (NGF) promotes sustained ERK activation and cell differentiation. These differences have typically been assumed to reflect distinct feedback mechanisms in the Raf-MEK-ERK signaling network, with the receptors themselves acting as simple upstream inputs. We failed to confirm the expected differences in feedback type when investigating transient versus sustained signaling downstream of the EGF receptor (EGFR) and NGF receptor (TrkA). Instead, we found that ERK signaling faithfully followed RTK dynamics when receptor signaling was modulated in different ways. EGFR activation was switched from transient to sustained when receptor internalization was inhibited with drugs or mutations, or in a chimeric receptor likely to have impaired dimerization, and ERK activation kinetics followed. EGFR signaling also became more sustained upon addition of sub-stoichiometric levels of the EGFR inhibitor erlotinib to reduce kinase activation lifetime. Again, ERK signaling dynamics followed receptor activation kinetics. Our results argue that RTK activation kinetics play a crucial role in determining MAP kinase cascade signaling dynamics and cell fate decisions and that signaling outcome can be selected by activating a given RTK in different ways.
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影响因子：
64.5
作者：
Ho CCM;Chhabra A;Starkl P;Schnorr PJ;Wilmes S;Moraga I;Kwon HS;Gaudenzio N;Sibilano R;Wehrman TS;Gakovic M;Sockolosky JT;Tiffany MR;Ring AM;Piehler J;Weissman IL;Galli SJ;Shizuru JA;Garcia KC
通讯作者：
Garcia KC
影响因子：
9.2
作者：
DIKIC, I;SCHLESSINGER, J;LAX, I
通讯作者：
LAX, I
影响因子：
48
作者：
Gibson, Daniel G.;Young, Lei;Smith, Hamilton O.
通讯作者：
Smith, Hamilton O.
影响因子：
4.8
作者：
Harper, Callista B.;Martin, Sally;Meunier, Frederic A.
通讯作者：
Meunier, Frederic A.
影响因子：
64.5
作者：
Freed DM;Bessman NJ;Kiyatkin A;Salazar-Cavazos E;Byrne PO;Moore JO;Valley CC;Ferguson KM;Leahy DJ;Lidke DS;Lemmon MA
通讯作者：
Lemmon MA