Essence of Cancer Biology: Disruption of Stress-fibers upon Malignant Transformation

Around 1974, at Cold Spring Harbor (CSH) Symposium on Tumor Viruses, Klaus Weber (and his colleagues) presented a “historical” paper on SV40-induced disruption of actin stress fibers in fibroblasts. SV40 is an oncogenic virus which carries the T-antigen that causes malignant transformation of normal cells such as fibroblasts. Using fluorescent antibodies against actin and myosin, they revealed that stress fibers, which consist of both actin filaments and myosin filaments, disappear  upon SV40-induced malignant transformation of fibroblasts (1).

This sensational finding prompted so many young biochemists or cancer scientists around the world to study the relationship between this cytoskeleton and malignant transformation. I was among these youth working at NIH, and in 1977 we discovered a new kinase that phosphorylates the heavy chain of a single-headed  myosin (myosin I) from a soil amoeba. This kinase is essential for the actin-activation of this myosin ATPase. Later this myosin I heavy chain kinase is among PAK (RAC/CDC42-activated kinase) family kinases, and both PAK1 and PAK4 are essential for the growth of malignant cells.   

Around 1983 at Max-Planck-Institute in Muenchen, we discovered another new kinase called “CAP42 kinase” in Physarum.  CAP42 is a heterodimer consisting of CAP42 (a) and CAP42 (b), and caps the “barbed” (plus) end of actin filaments, leading to a rapid de-polymerization of actin filaments at “pointed” (minus) end.  Capping by CAP42 is Ca²⁺-independent, but the phosphorylated (p) CAP42 requires Ca²⁺ for its capping. 

The phosphorylation takes place only at CAP42 (b), and is inhibited by actin and Ca²⁺. Furthermore, CAP42 (b), but not CAP42(a) binds DNase, as does actin.  In the end, CAP42 (b) was identified as actin, while CAP42 (a) is fragmin, an F-actin capping/severing protein of 42 kDa. Thus, “CAP42 kinase”  was renamed “Actin-Fragmin kinase” (AFK) or simply Physarum actin kinase (AK). Is there any actin kinase in mammalian cells? 

Yes, in 1986, a Japanese group found that actin is phosphorylated by CK1 (casein kinase 1) in vitro, and in 2002, a Greek group unvailed that PAK1 phosphorlates actin in mammalian cells. Thus, in mammals at least two distinct actin kinases (AKs), both of which are oncogenic. PAK1 phosphorylates both myosin and actin, while CK1 phosphorylates only actin so far.  Also it was confirmed a few years ago that SV40 T-antigen activates both PAK1 and CK1.   

Thus, it is most likely that these two kinases (PAK1 and CK1) are involved in the SV40-induced disruption of actin stress fibers upon the malignant transformation of fibroblasts that was reported by Klaus Weber et al. more than 4 decades ago. 

Klaus Weber (born in 1936) is a brilliant  German biochemist, and in my opinion, he would deserve a Nobel-prize in Physiology/Medicine for his development of a variety of popular cutting-edge biotechnologies such as SDS-PAGE, immunofluorescent staining of cytoskeleton, and SiRNA-based gene silencing. 

References:

1. R Pollack, M Osborn, and K Weber. Patterns of organization of actin and myosin in normal and transformed cultured cells. Proc Natl Acad Sci U S A. 1975; 72(3): 994–8.