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Book reviews 67The place of these important tools for medical practice, education and research and as aids to the enlightenment of patients is well explained and fully expressedThe authors have carried out an excellent, timely and scholarly review of iatrogenic illness. It is my hope that they will examine in a subsequent book such topics as commerciogenic medical harm (marketing of medicines and infant formula) mediogenic medical harm (premature proclamation of "breakthroughs" and unbalanced scare stories) political medical harm (subordination of health care to weaponry, and medical involvement with torture), and ideological medical harm (denial of medical care to women, sanctity of life, abortion, euthanasia, terminal care).

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Differentiation of PC12 cells by nerve growth factor (NGF) requires the activation of various mitogen-activated protein kinases (MAPKs) including p38 MAPK. Accumulating evidence has suggested cross-talk regulation of NGF-induced responses by G protein-coupled receptors, thus we examined whether NGF utilizes G(i/o) proteins to regulate p38 MAPK in PC12 cells. Induction of p38 MAPK phosphorylation by NGF occurred in a time- and dose-dependent manner and was partially inhibited by pertussis toxin (PTX). NGF-dependent p38 MAPK phosphorylation became insensitive to PTX treatment upon transient expressions of Galpha(z) or the PTX-resistant mutants of Galpha(i2) and Galpha(oA). Moreover, Galpha(i2) was co-immunoprecipitated with the TrkA receptor from PC12 cell lysates. To discern the participation of various signaling intermediates, PC12 cells were treated with a panel of specific inhibitors prior to the NGF challenge. NGF-induced p38 MAPK phosphorylation was abolished by inhibitors of Src (PP1, PP2, and SU6656) and MEK1/2 (U0126). Inhibition of the p38 MAPK pathway also suppressed NGF-induced PC12 cell differentiation. In contrast, inhibitors of JAK2, phospholipase C, protein kinase C and Ca(2+)/calmodulin-dependent kinase II did not affect the ability of NGF to activate p38 MAPK. Collectively, these studies indicate that NGF-dependent p38 MAPK activity may be mediated via G(i2) protein, Src, and the MEK/ERK cascade.

Accumulating evidence indicates that G protein signaling plays an active role in the regulation of cell survival. Our previous study demonstrated the regulatory effects of Gi/o proteins in nerve growth factor‐induced activation of pro‐survival Akt kinase. In the present study we explored the role of various members of the Gs, Gq/11 and G12/13 subfamilies in the regulation of Akt in cultured mammalian cells. In human embryonic kidney 293 cells transiently expressing constitutively active mutants of Gα11, Gα14, Gα16, Gα12, or Gα13 (Gα11QL, Gα14QL, Gα16QL, Gα12QL and Gα13QL, respectively), basal phosphorylation of Akt was attenuated, as revealed by western blotting analysis using a phosphospecific anti‐Akt immunoglobulin. In contrast, basal Akt phosphorylation was unaffected by the overexpression of a constitutively active Gαs mutant (GαsQL). Additional experiments showed that Gα11QL, Gα14QL, Gα16QL, Gα12QL and Gα13QL, but not GαsQL, attenuated phosphorylation of the Akt‐regulated translation regulator tuberin. Moreover, they were able to inhibit the epidermal growth factor‐induced Akt activation and tuberin phosphorylation. The inhibitory mechanism of Gq family members was independent of phospholipase Cβ activation and calcium signaling because Gα11QL, Gα14QL and Gα16QL remained capable of inhibiting epidermal growth factor‐induced Akt activation in cells pretreated with U73122 and the intracellular calcium chelator, BAPTA/AM. Finally, overexpression of the dominant negative mutant of RhoA blocked Gα12QL‐ and Gα13QL‐mediated inhibition, suggesting that activated Gα12 and Gα13 inhibit Akt signaling via RhoA. Collectively, this study demonstrated the inhibitory effect of activated Gα11, Gα14, Gα16, Gα12 and Gα13 on pro‐survival Akt signaling.

Tuberin, a tumor suppressor protein, is involved in various cellular functions including survival, proliferation, and growth. It has emerged as an important effector regulated by receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs). Regulation of tuberin by RTKs and GPCRs is highly complex and dependent on the type of receptors and their associated signaling molecules. Apart from Akt, the first kinase recognized to phosphorylate and inactivate tuberin upon growth factor stimulation, an increasing number of kinases upstream of tuberin have been identified. Furthermore, recruitment of different scaffolding adaptor components to the activated receptors appears to play an important role in the regulation of tuberin activity. More recently, the differential regulation of tuberin by various G protein family members have also been intensively studied, it appears that G proteins can both facilitate (e.g., G_i/o) as well as inhibit (e.g., G_q) tuberin phosphorylation. In the present review, we attempt to summarize our emerging understandings of the roles of RTKs, GPCRs, and their cross-talk on the regulation of tuberin.

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