Trihydrophobin 1（TH1) : a Tumor Suppressor that Directly Inhibits the Kinase PAK1

TH1 gene is a relatively ubiquitous gene that is present from Drosophila
to human beings (but absent in nematodes). In 2004 Jianxin Gu's group at
Fudan University in Shanghai found that TH1 protein inactivates the kinase
A-Raf somehow, In 2009 the same group revealed that TH1 protein directly
inhibits the kinase activity of PAK1 by binding the C-terminal kinase domain,
suggesting that TH1 protein is a tumor suppressor, as is Merlin/NF2 that
also directly inhibits the oncogenic kinase PAK1 (Hirokawa et al, 2004).

Interestingly, an E3 ubiquitin ligase of human papilloma virus (HPV) called
E6-AP was found to inactivate TH1 protein by ubiquitination (Yang et al,
2007). According to the 2008 Nobel laureate, Harald zur Hausen at German
Cancer Research Center (DKFZ), HPV is the major cause of cervical cancers.

Thus, it is likely that this virus abnormally activates PAK1 by inactivating
TH1. In other words the majority of cervical cancers are among PAK1-dependent
cancers. This notion suggests the possibility that the potent anti-PAK1
drugs such as FK228 and Bio 30 would suppress the growth of cervical cancers,
as other PAK1-dependent cancers and NF tumors.

In this context, it should be worth noting that vitamin K2, in particular
menaquinon-7, derived from "natto" (fermented sticky soy beans), a Japanese
traditional cuisine, appears to inactivate the kinase PAK1 somehow, as it
blocks the growth of PAK1-dependent cancers, metastasis and angiogenesis,
without up-regulating p27 (CDK inhibitor), down-regulation of which requires
the kinase AKT (Shibayama-Imazu et al, 2003; Liu et al, 2007). Thus, there
is a possibility that these PAK1-dependent cancers and NF tumors could be
treated at home, simply by taking "natto" every day, in near future.

The best "natto" brand (from Mizkan) contains 1700 micro g of menaquinone-7
per 100 g, and probably 40 g (the minimum package) of this "natto" daily
would be sufficient for the treatment. This small package costs only 40
cents in Japan which is even less expensive than 5 ml of Bio 30 costing
around US$1.00. If "natto" is not available at your local oriental shop,
you could make "natto" at home, by mixing steamed/boiled soy beans with
spores of Bacillus subtilis var natto, and incubating at 42oC for a few days.


J Biol Chem. 2009 Jan 9.

Trihydrophobin 1（TH1) interacts with PAK1 and regulates ERK/MAPK activation
and cell migration.

Cheng C, Kong X, Wang H, Gan H, Hao Y, Zou W, Wu J, Chi Y, Yang J, Hong
Y, Chen K, Gu J.

Gene Research Center, Shanghai Medical College of Fudan University, Shanghai,
Shanghai 200032.

PAK activity has been shown to be required for maximal activation of the
oncogenic RAF-MEK-MAPK signaling cascade, due to PAK co-activation of RAF
and MEK.

Trihydrophobin 1 (TH1), previously identified as a negative regulator of
the kinase A-RAF, also interacted with PAK1 in cultured cells. Confocal
microscopy assay indicated that TH1 colocalized with PAK1 in both cytoplasm
and nucleus. GST-pull down and coimmunoprecipitation experiments demonstrated
TH1 directly interacted with PAK1 and bound selectively to the carboxyl
kinase domain of PAK1 and the ability of the binding was enhanced along
with activation of PAK1. The binding pattern of PAK1 implied that this interaction
was mediated in part by the PAK1 kinase activity.

TH1 inhibited PAK1 kinase activity and negatively regulated MAPK signal
transduction.