PAR-6-PAR-3 mediates Cdc42-induced Rac activation through the Rac GEFs STEF/Tiam1
PAR-6-PAR-3 mediates Cdc42-induced Rac activation through the Rac GEFs STEF/Tiam1
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DOI：
10.1038/ncb1227
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发表时间：
2005-03-01
影响因子：
21.3
通讯作者：
Kaibuchi, K
中科院分区：
文献类型：
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作者：
Nishimura, T;Yamaguchi, T;Kaibuchi, K
PAR-3、PAR-6和非典型蛋白激酶C（aPKC）的极性复合物在各种细胞极化事件中发挥作用，包括神经元特化（1-4）。小的GTdR Cdc 42与PAR-6结合并调节细胞极性。然而，关于Cdc 42- PAR蛋白复合物的下游信号知之甚少。在此，我们发现PAR-3直接与RAc特异性鸟嘌呤核苷酸交换因子STEF/Tiam 1相互作用，并且STEF与PAR-3 - aPKC - PAR-6 -Cdc 42-GTP形成复合物。Cdc 42以Rac依赖的方式在N1 E-115神经母细胞瘤细胞中诱导板状伪足。破坏Cdc 42 PAR- 6或PAR- 3 - STEF结合抑制Cdc 42诱导的板状伪足，但不丝状伪足。分离的STEF结合PAR-3片段足以诱导独立于Cdc 42和PAR-6的片状伪足。PAR-3是Cdc 42诱导的Rac激活所必需的，但不是板状伪足形成本身所必需的。在培养的海马神经元中，STEF积累在生长轴突的尖端，并与PAR-3共定位。Cdc 42- PAR- 6 - PAR-3 - STEF/Tiam 1- Rac的时空激活和信号转导似乎参与了神经突生长和轴突特化。我们建议PAR- 6 - PAR- 3复合物介导Cdc 42诱导的Rac激活的STEF/Tiam 1的装置，这一过程似乎是必要的建立神经元极性。
A polarity complex of PAR-3, PAR-6 and atypical protein kinase C ( aPKC) functions in various cell-polarization events, including neuron specification(1-4). The small GTPase Cdc42 binds to PAR-6 and regulates cell polarity. However, little is known about the downstream signals of the Cdc42 - PAR protein complex. Here, we found that PAR-3 directly interacted with STEF/Tiam1, which are Rac-specific guanine nucleotide-exchange factors, and that STEF formed a complex with PAR-3 - aPKC - PAR-6 - Cdc42-GTP. Cdc42 induces lamellipodia in a Rac-dependent manner in N1E-115 neuroblastoma cells. Disruption of Cdc42 PAR- 6 or PAR- 3 - STEF binding inhibited Cdc42-induced lamellipodia but not filopodia. The isolated STEF-binding PAR-3 fragment was sufficient to induce lamellipodia independently of Cdc42 and PAR-6. PAR-3 is required for Cdc42-induced Rac activation, but is not essential for lamellipodia formation itself. In cultured hippocampal neurons, STEF accumulated at the tip of the growing axon and colocalized with PAR-3. The spatio-temporal activation and signalling of Cdc42 - PAR- 6 - PAR-3 - STEF/Tiam1 - Rac seem to be involved in neurite growth and axon specification. We propose that the PAR- 6 - PAR- 3 complex mediates Cdc42-induced Rac activation by means of STEF/Tiam1, and that this process seems to be required for the establishment of neuronal polarity.