Creation of a stress-activated p90 ribosomal S6 kinase. The carboxyl-terminal tail of the MAPK-activated protein kinases dictates the signal transduction pathway in which they function.

Mitogen-activated protein kinase-activated protein kinases (MAPKAPKs) lie immediately downstream of the mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK), and p38 MAPK. Although the family of MAPKAPKs shares sequence similarity, it demonstrates selectivity for the upstream activator. Here we demonstrate that each of the ERK- and p38 MAPK-regulated MAPKAPKs contains a MAPK docking site positioned distally to the residue(s) phosphorylated by MAPKs. The isolated MAPK docking sites show specificity for the upstream activator similar to that reported for the full-length proteins. Moreover, replacement of the ERK docking site of p90 ribosomal S6 kinase with the p38 MAPK docking site of MAPKAPK2 converts p90 ribosomal S6 kinase into a stress-activated kinase in vivo. It is apparent that mechanisms controlling events downstream of the proline-directed MAPKs involve specific MAPK docking sites within the carboxyl termini of the MAPKAPKs that determine the cascade in which the MAPKAPK functions.

Generation of constitutively active p90 ribosomal S6 kinase in vivo. Implications for the mitogen-activated protein kinase-activated protein kinase family.

p90 ribosomal S6 kinases (RSKs), containing two distinct kinase catalytic domains, are phosphorylated and activated by extracellular signal-regulated kinase (ERK). The amino-terminal kinase domain (NTD) of RSK phosphorylates exogenous substrates, whereas the carboxyl-terminal kinase domain (CTD) autophosphorylates Ser-386. A conserved putative autoinhibitory alpha helix is present in the carboxyl-terminal tail of the RSK isozymes ((697)HLVKGAMAATYSALNR(712) of RSK2). Here, we demonstrate that truncation (Delta alpha) or mutation (Y707A) of this helix in RSK2 resulted in constitutive activation of the CTD. In vivo, both mutants enhanced basal Ser-386 autophosphorylation by the CTD above that of wild type (WT). The enhanced Ser-386 autophosphorylation was attributed to disinhibition of the CTD because a CTD dead mutation (K451A) eliminated Ser-386 autophosphorylation even in conjunction with Delta alpha and Y707A. Constitutive activity of the CTD appears to enhance NTD activity even in the absence of ERK phosphorylation because basal phosphorylation of S6 peptide by Delta alpha and Y707A was approximately 4-fold above that of WT. A RSK phosphorylation motif antibody detected a 140-kDa protein (pp140) that was phosphorylated upon epidermal growth factor or insulin treatment. Ectopic expression of Delta alpha or Y707A resulted in increased basal phosphorylation of pp140 compared with that of WT, presenting the possibility that pp140 is a novel RSK substrate. Thus, it is clear that the CTD regulates NTD activity in vivo as well as in vitro.

Arteritis following protracted supervoltage pelvic irradiation. Report of a case.

Arterial injuries attributed to irradiation are most frequent about the head and neck and are invariably triggered by infection, infarction, or fistulas. Vascular changes from surgery or invasive behavior of tumor can also contribute to local vascular insufficiencies. It is quite possible in humans that irradiation can accelerate the aging processes in atherosclerotic vessels. The case reported is unusual in that rather routine, postoperative, pelvic irradiation was given for pelvic soft tissue and bone carcinomatosis, only to be followed in 6 months to 1 year by vascular insufficiency symptoms in the lower extremities. Symptoms progressed to the point that surgical correction was contemplated, but then postponed when signs and symptoms improved following cessation of smoking. The patient had had no previous history of a Reynaud's diathesis. Although histologic proof is lacking (patient continues to do generally quite well 5 years following palliative treatment), field films and subsequent angiographic abnormalities can be superimposed almost exactly. Neither author is entirely happy with the diagnosis of 'radiation arteritis' for the reasons discussed, but the coincidence of radiation fields and areas of arterial damage makes the role of irradiation indicating.

Diagnosis and surgical treatment of page kidney: Selected aspects.

The Page kidney is a well-recognized cause of correctable hypertension. The case described herein illustrates certain select diagnostic features including the method of radiographic visualization of the capsule and subcapsular fluid-which appears to be related to both the volume of contrast material injected and the proper timing sequence of the radiographic examination. The chosen therapeutic approach was aimed at curing the hypertension while preserving maximal renal function. Aspiration therapy was used as an initial conservative procedure. Removal of the entire pseudocapsule followed in preference to nephrectomy.

Angioplastic repair of a ruptured pulmonary artery aneurysm.

A 28-year-old woman had a ruptured solitary pulmonary arterial aneurysm which was successfully treated by pericardial patch graft. The etiology of the aneurysm could not be determined although the patient had had several episodes of blunt chest trauma in the past. Unusual aspects of this case include: location of the aneurysm in the intermediate portion of the left pulmonary artery within the major intralobar fissure, intrapleural rupture, preoperative diagnosis by pulmonary angiography, and an incidentally discovered histopathological abnormality of the aneurysm itself for which no satisfactory explanation has been found.