The p85 isoform of the kinase S6K1 functions as a secreted oncoprotein to facilitate cell migration and tumor growth.
The p85 isoform of the kinase S6K1 functions as a secreted oncoprotein to facilitate cell migration and tumor growth.
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激酶 S6K1 的 p85 亚型充当分泌性癌蛋白，促进细胞迁移和肿瘤生长
DOI：
10.1126/scisignal.aao1052
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发表时间：
2018-03-27
影响因子：
7.3
通讯作者：
Wei W
中科院分区：
文献类型：
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作者：
Zhang J;Guo J;Qin X;Wang B;Zhang L;Wang Y;Gan W;Pandolfi PP;Chen W;Wei W
乳腺癌细胞可能会释放S6K1的P85亚型，作用于周围细胞，促进肿瘤生长。致癌激酶癌细胞通过不同途径向其他癌细胞和未转化细胞发出信号，从而产生适合其生长的环境。张某等人。注意到P85是促生长蛋白S6K1最长的异构体，在其N端有一个6-精氨酸残基，在较短的异构体中不存在。这个基序类似于HIV Tat蛋白中的一个基序，使其能够从细胞中释放并进入周围细胞。在培养的乳腺癌或未转化的细胞中，将S6K1的P85亚型添加到培养液中可以增强S6K1靶标的磷酸化，并增强癌细胞的特征行为，如细胞大小和迁移。此外，将这种S6K1亚型注射到小鼠体内，增加了由乳腺癌细胞形成的异种移植瘤的生长和转移。由于S6K1基因在一些乳腺癌中被放大，针对这种较长的异构体的抗体可能会抑制肿瘤的生长和转移。癌细胞可以通过分泌教育周围基质细胞的蛋白质来重塑周围的微环境，以促进细胞的生长、侵袭和迁移。我们报道了S6K(核糖体蛋白S6激酶)最长的异构体p85S6K1，而不是较短的异构体p70S6K1或p56S6K2，它是通过其类似HIV的Tat基序，N端6-精氨酸基序从癌细胞中分泌出来的。外源产生的p85S6K1蛋白进入培养的转化和未转化细胞，促进或赋予恶性行为，导致细胞生长和迁移增加。当注射到小鼠体内时，p85S6K1蛋白促进了移植的乳腺癌细胞的生长和肺转移。因此，我们的发现揭示了p85S6K1作为一种分泌型致癌激酶的作用，并提供了一种机制，通过改变周围细胞来驱动肿瘤发生，从而重塑其微环境。
Breast cancer cells may release the p85 isoform of S6K1 to act in surrounding cells and promote tumor growth. Messaging by oncogenic kinase Cancer cells generate an environment amenable for their growth by signaling through various pathways to other cancer cells and nontransformed cells. Zhang et al. noticed that p85, the longest isoform of the growth-promoting kinase S6K1, had a six-arginine residue motif in its N terminus that was not present in shorter isoforms. This motif resembles a motif in the HIV TAT protein that enables it to be released from cells and enter surrounding cells. In cultured breast cancer or nontransformed cells, adding the p85 isoform of S6K1 to the medium enhanced the phosphorylation of S6K1 targets and behaviors characteristic of cancer cells, such as increased cell size and migration. Furthermore, injection of this S6K1 isoform into mice increased the growth and metastasis of xenografts formed by breast cancer cells. Because the S6K1 gene is amplified in some breast cancers, an antibody that targets this longer isoform may attenuate tumor growth and metastasis. Cancer cells can remodel surrounding microenvironments to facilitate cell growth, invasion, and migration by secreting proteins that educate surrounding stromal cells. We report that p85S6K1, the longest isoform of S6K (ribosomal protein S6 kinase), but not the shorter isoform p70S6K1 or p56S6K2, was secreted from cancer cells through its HIV TAT-like, N-terminal six-arginine motif. The exogenously produced p85S6K1 protein entered cultured transformed and nontransformed cells to promote or confer malignant behaviors, leading to increased cell growth and migration. When injected into mice, the p85S6K1 protein enhanced the growth of xenografted breast cancer cells and lung metastasis. Hence, our findings reveal a role for p85S6K1 as a secreted oncogenic kinase and provide a mechanism by which cancer cells remodel their microenvironment by transforming the surrounding cells to drive tumorigenesis.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
82.9
作者：
通讯作者：
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影响因子：
4
作者：
Berven, LA;Crouch, MF
通讯作者：
Crouch, MF
影响因子：
11.4
作者：
Shima, H;Pende, M;Kozma, SC
通讯作者：
Kozma, SC
影响因子：
64.8
作者：
通讯作者：
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