RESUMO
Despite abundant data supporting c-Src as a metastasis-promoting oncogene, activating mutations of c-Src are rare. This suggests that trans-interacting proteins may have a critical role in regulating c-Src activation. Here, we first report the discovery of Src homology 3 (SH3) domain-binding glutamic acid-rich-like protein (SH3BGRL), a novel c-Src activator in mice. Ectopic expression of murine SH3BGRL (mSH3BGRL) strongly promoted both tumor cell invasion and lung metastasis. Molecularly, mSH3BGRL specifically bound the inactive form of c-Src phosphorylated at Tyr527, promoting Tyr416 phosphorylation of c-Src and subsequent FAK-mediated activation of ERK and AKT signaling pathways. Targeting endogenous c-Src alone was sufficient to abolish mSH3BGRL-induced cancer metastasis in vivo. Unexpectedly, human SH3BGRL (hSH3BGRL) in turn suppressed tumorigenesis and metastasis in nature. We attempted site-specific reversion of hSH3BGRL amino-acid sequence to mSH3BGRL and found V108A substitution sufficient to restore SH3BGRL function as a c-Src activator and metastasis promoter. Notably, the somatic mutation R76C of hSH3BGRL can similarly act as hSH3BGRL-V108A and mSH3BGRL in tumorigenesis and metastasis. Our results uncover an evolutionarily controversial role of SH3BGRL in driving tumor metastasis through c-Src activation, and suggests that hSH3BGRL mutation status could be relevant to cancer diagnosis and therapy.
Assuntos
Neoplasias/genética , Oncogenes/genética , Proteínas/genética , Proteínas Supressoras de Tumor/genética , Sequência de Aminoácidos , Animais , Western Blotting , Células CHO , Linhagem Celular Tumoral , Movimento Celular/genética , Cricetinae , Cricetulus , Humanos , Células MCF-7 , Camundongos Nus , Mutação , Metástase Neoplásica , Neoplasias/metabolismo , Neoplasias/patologia , Ligação Proteica , Proteínas/metabolismo , Proteínas Proto-Oncogênicas pp60(c-src)/genética , Proteínas Proto-Oncogênicas pp60(c-src)/metabolismo , Interferência de RNA , Homologia de Sequência de Aminoácidos , Transdução de Sinais/genética , Transplante HeterólogoRESUMO
The aim of the present study was to investigate the influence of a 25-min time interval between the first and the last reading of a series of six, on systolic (SBP) and Phase V diastolic (DBP) blood pressure and its implications for prevalence rates of hypertension. Readings were taken from 5999 persons (2889 men and 3110 women) by two observers using a Hawksley random-zero sphygmomanometer. The first reading was taken 5 min after entering the examining room. The study showed a considerable fall in mean SBP (men, 10.3 mmHg; women, 10.4 mmHg) and hardly a difference in mean DBP (men, 0.8 mmHg; women, 0.1 mmHg) between the first and sixth reading. The fall in SBP was independent of observer and sex and hardly correlated with age or Quetelet's index. The study also showed the implications for the classification of hypertension. Prevalence rates of isolated systolic hypertension dropped remarkably (men, 4.0 to 0.5%; women, 0.9 to 0.1%) between both readings while prevalence rates of severe, moderate and mild diastolic hypertension were nearly similar for the first and sixth reading.
