Trihydrophobin 1 (TH1): a tumor suppressor that inactivates the kinase PAK1, and is blocked by the oncogenic kinase SRC.

For a decade since 2002, Jianxin Gu’s group at Fudan University in Shanghai has extensively studied the biological function of an ubiquitous protein called trihydrophobin 1 (TH1), present in a variety of animals from Drosophila to human, and found that TH1 inactivates the oncogenic kinase PAK1 and its downstream effectors MEK/ERK as well (1, 2), and is inactivated by the oncogenic Tyr-kinase SRC which phosphorylates Tyr 6 of TH1 (2). In addition, TH1 inactivates another oncogenic kinase A-Raf, but neither B-Raf nor C-Raf (3). Over-expression of TH1 in breast cancer cells blocks both their growth and migration which depend on PAK1 (4). Thus, like Merlin, TH1 is a tumor suppressor that down-regulates PAK1 and its effectors, and its dysfunction probably causes cancer development, and shortens our lifespan.

Back to 2000, we found that PP1, an inhibitor of SRC family kinases, blocks the activation of PAK1, with the IC50 around 10 nM, and the PAK1-dependent growth of RAS-transformants such as pancreatic and colon cancers (5). Recently it was found that the major target of PP1 is FYN, a member of SRC family.  Thus, PP1 reactivates TH1 by blocking FYN, and TH1 in turn inactivates PAK1…

In this context, it should be worth noting that EGF, a ligand for the cell surface Tyr-kinase ErbB1 (EGF receptor), stimulates the TH1 phosphorylation by SRC family kinases, clearly indicating that SRC acts downstream of ErbB1 (2). We found that inactivation of PAK1 by PP1 is not affected by AG 1478, an ErbB1-specific inhibitor, but markedly enhanced by AG 879, an inhibitor of ETK, another Tyr-kinase (6, 7), strongly suggesting that the PP1-induced PAK1 inactivation involves the TH1 phosphorylation by FYN. The combination of PP1 and AG 879 completely blocks both PAK1 and the growth of RAS-transformants in vivo (xenografts mice).

References:

1. Cheng, CM., Kong, XF., Wang, HZ., Gan, HC. et al. Trihydrophbin 1 interacts with
PAK1 and regulates ERK/MAPK activation and cell migration. J. Biol. Chem. 2009,
284, 8786-96.

2. Wu, W., Sun, Z., Wu, J., Peng, X. et al. Trihydrophobin 1 Phosphorylation by c-Src
Regulates MAPK/ERK Signaling and Cell Migration. PLoS One. 2012, 7, e29920.

3. Liu, W., Shen, WY., Yang, YZ., Yin, XL. et al. Trihydrophobin 1 Is a New Negative
Regulator of A-Raf Kinase. J. Biol. Chem 2004, 279, 10167-75.

4. Zou, WY., Yang, YZ., Wu, YH., Sun, LL. et al. Negative role of trihydrophobin 1
in breast cancer growth and migration. Cancer Sci. 2010, 101, 2156–62.

5. He, H., Hirokawa, Y., Levitzki, A., Maruta, H. An anti-Ras cancer potential of PP1,
an inhibitor specific for Src family kinases: in vitro and in vivo studies. Cancer J.
2000, 6, 243-8.

6. He, H., Hirokawa, Y., Manser, E., Lim, L. et al. Signal therapy for RAS induced
cancers in combination of AG 879 and PP1, specific inhibitors for ErbB2 and Src
family kinases, that block PAK activation. Cancer J. 2001, 7, 191-202.

7. He, H., Hirokawa, Y., Gazit, A., Yamashita, Y. et al. The Tyr-kinase inhibitor AG879,
　that blocks the ETK-PAK1 interaction, suppresses the RAS-induced PAK1activation
and malignant transformation. Cancer Biol Ther. 2004, 3, 96-101.