不同 ShcA 信号复合物的整合促进乳腺肿瘤生长和酪氨酸激酶抑制剂抗性,Molecular Cancer Research

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不同 ShcA 信号复合物的整合促进乳腺肿瘤生长和酪氨酸激酶抑制剂抗性
Molecular Cancer Research ( IF 4.1 ) Pub Date : 2018-02-16 , DOI: 10.1158/1541-7786.mcr-17-0623
Jacqueline R Ha _{1,

2} , Ryuhjin Ahn _{1,

2} , Harvey W Smith _{3,

4} , Valerie Sabourin ₁ , Steven Hébert ₁ , Eduardo Cepeda Cañedo _{1,

2} , Young Kyuen Im _{1,

2} , Claudia L Kleinman _{1,

5} , William J Muller _{3,

5} , Josie Ursini-Siegel _{1,

2,

3,

4,

6}

Affiliation

大多数磷酸酪氨酸信号网络之间的共同点是它们共同使用适配器蛋白来转导有丝分裂信号。ShcA (SHC1) 是一种这样的衔接蛋白，它采用两个磷酸酪氨酸结合域（PTB 和 SH2）和关键的磷酸酪氨酸残基来促进乳腺肿瘤发生。受体酪氨酸激酶 (RTK)，例如 ErbB2，结合 ShcA PTB 结构域，通过与 ShcA 酪氨酸磷酸化位点下游的 Grb2 结合以激活 AKT/mTOR 信号传导来促进乳腺肿瘤发生。然而，乳腺肿瘤也依赖于 ShcA PTB 域来结合许多限制次级有丝分裂信号网络激活的负调节因子。这项研究检查了 PTB 非依赖性 ShcA 池在控制乳腺肿瘤生长和对酪氨酸激酶抑制剂的抗性中的作用。我们证明不依赖 PTB 的 ShcA 复合物主要依赖 ShcA SH2 域来激活 ErbB2 阳性乳腺癌中的多种 Src 家族激酶 (SFK)，包括 Src 和 Fyn。使用遗传和药理学方法，我们表明不依赖 PTB 的 ShcA 复合物通过以 SH2 依赖性方式增加 Src 和 Fyn 酪氨酸激酶的活性来增加乳腺肿瘤的发生。这种来自不同 ShcA 池的信号复合物的分叉转导非冗余信号，这些信号整合了 AKT/mTOR 和 SFK 通路，以协同增加乳腺肿瘤的生长和对酪氨酸激酶抑制剂（包括拉帕替尼和 PP2）的抵抗力。这项研究从机制上剖析了不同细胞内 ShcA 复合物之间的相互作用如何影响酪氨酸激酶组以影响乳腺肿瘤发生。含义：ShcA 接头在不同的信号复合物中影响酪氨酸激酶信号、乳腺肿瘤生长和对酪氨酸激酶抑制剂的抗性。摩尔癌症研究；16(5); 894-908。©2018 AACR。

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Integration of distinct ShcA signaling complexes promotes breast tumor growth and tyrosine kinase inhibitor resistance

The commonality between most phospho-tyrosine signaling networks is their shared use of adaptor proteins to transduce mitogenic signals. ShcA (SHC1) is one such adaptor protein that employs two phospho-tyrosine binding domains (PTB and SH2) and key phospho-tyrosine residues to promote mammary tumorigenesis. Receptor tyrosine kinases (RTK), such as ErbB2, bind the ShcA PTB domain to promote breast tumorigenesis by engaging Grb2 downstream of the ShcA tyrosine phosphorylation sites to activate AKT/mTOR signaling. However, breast tumors also rely on the ShcA PTB domain to bind numerous negative regulators that limit activation of secondary mitogenic signaling networks. This study examines the role of PTB-independent ShcA pools in controlling breast tumor growth and resistance to tyrosine kinase inhibitors. We demonstrate that PTB-independent ShcA complexes predominately rely on the ShcA SH2 domain to activate multiple Src family kinases (SFK), including Src and Fyn, in ErbB2-positive breast cancers. Using genetic and pharmacologic approaches, we show that PTB-independent ShcA complexes augment mammary tumorigenesis by increasing the activity of the Src and Fyn tyrosine kinases in an SH2-dependent manner. This bifurcation of signaling complexes from distinct ShcA pools transduces non-redundant signals that integrate the AKT/mTOR and SFK pathways to cooperatively increase breast tumor growth and resistance to tyrosine kinase inhibitors, including lapatinib and PP2. This study mechanistically dissects how the interplay between diverse intracellular ShcA complexes impacts the tyrosine kinome to affect breast tumorigenesis. Implications: The ShcA adaptor, within distinct signaling complexes, impacts tyrosine kinase signaling, breast tumor growth, and resistance to tyrosine kinase inhibitors. Mol Cancer Res; 16(5); 894–908. ©2018 AACR.

更新日期：2018-02-16

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