The skeletal muscle specific Ca 2؉ /calmodulin-dependent protein kinase (CaMKII␤ M ) is localized to the sarcoplasmic reticulum (SR) by an anchoring protein, ␣KAP, but its function remains to be defined. Protein interactions of CaMKII␤ M indicated that it exists in complex with enzymes involved in glycolysis at the SR membrane. The kinase was found to complex with glycogen phosphorylase, glycogen debranching enzyme, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and creatine kinase in the SR membrane. CaMKII␤ M was also found to assemble with aldolase A, GAPDH, enolase, lactate dehydrogenase, creatine kinase, pyruvate kinase, and phosphorylase b kinase from the cytosolic fraction. The interacting proteins were substrates of CaMKII␤ M , and their phosphorylation was enhanced in a Ca 2؉ -and calmodulin (CaM)-dependent manner. The CaMKII␤ M could directly phosphorylate GAPDH and markedly increase (ϳ3.4-fold) its activity in a Ca 2؉ /CaMdependent manner. These data suggest that the muscle CaMKII␤ M isoform may serve to assemble the glycogenmobilizing and glycolytic enzymes at the SR membrane and specifically modulate the activity of GAPDH in response to calcium signaling. Thus, the activation of CaMKII␤ M in response to calcium signaling would serve to modulate GAPDH and thereby ATP and NADH levels at the SR membrane, which in turn will regulate calcium transport processes.Free calcium (Ca 2ϩ ) regulates diverse cellular functions by acting as an intracellular second messenger. A large part of these cellular functions are mediated by CaM, 1 which is the ubiquitous intracellular Ca 2ϩ receptor. The Ca 2ϩ ⅐CaM complex allosterically activates numerous proteins, including Ca 2ϩ /CaMdependent protein kinase II (CaMKII) (1). CaMKII is a multifunctional enzyme that is highly expressed in brain and muscle. The kinase is believed to serve important roles in synaptic transmission (2, 3), gene transcription (4, 5), cell growth (6), and control of excitation-contraction coupling (7-9).The subcellular distribution of CaMKII indicates cytosolic and membrane localizations in different tissues (10). In skeletal muscle, an isoform of CaMKII is targeted to the SR membrane by a non-kinase protein, ␣KAP (11, 12). Different studies have been conducted to determine whether membrane-bound CaM kinase could phosphorylate different substrate proteins by virtue of its proximity effects and thereby regulate SR function. Although the calcium release channel/ryanodine receptor (RyR) and the calcium pump/Ca 2ϩ -ATPase in skeletal muscle SR were shown to be substrates of CaMKII␤ (13, 14), there does not appear to be any clear effects on the regulation of functional activity of these proteins induced by such phosphorylation (7,8,(15)(16)(17). Moreover, there is clear evidence that the RyR and calcium pump are regulated by local ATP, Ca 2ϩ , and CaM through direct ligand binding (15)(16)(17). In this regard, both Ca 2ϩ and CaM are present at the SR, and the level of ATP is believed to be tightly controlled through a membrane-bound glycolytic mac...

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Pancreatic cancer is notorious for its late presentation, early and aggressive local invasion, metastatic potential, and poor outcome. It presents at a clinically advanced stage that precludes the possibility of surgical resection in most cases and shows constitutive resistance to chemotherapy and radiotherapy in others. As a result, mortality from this disease parallels its incidence rates.Recent breakthroughs in the molecular biology of pancreatic cancer have assisted in translational research, giving hope for individualized therapy and better disease management. Molecular biology tools are guiding early diagnosis, the assessment of prognosis, and isolation of novel, more effective therapeutic targets.This review discusses the signature mutations of pancreatic cancer, implications of these mutations to pancreatic cancer biology, their linked pathways, and recent advances in their understanding as biomarkers as diagnostic, prognostic, and therapeutic tools in dealing with this disease.

One of the major signaling pathways that determine the tumor aggression and patient outcome in pancreatic cancer is the transforming growth factor-beta (TGF-ß) pathway. It is inactivated at various levels in pancreatic cancer and plays a dual role in tumor initiation and progression. The Smad family of proteins transduce signals from the TGF-ß superfamily ligands that regulate cell proliferation, differentiation and death through activation of receptor serine/threonine kinases. This review discusses the structure, function and regulation of various participating Smad family members, and their individual roles in determining the progression and outcome of pancreatic cancer patients, with a special emphasis on Smad4.

Most SMAD4 mutations are located in the mutational hotspot, mutation cluster region, present within MH2 domain. SMAD4 mutations affect Smad4 protein expression to different extents, depending on their location within the gene. SMAD4 gene alterations predict a worse outcome for patients with PDAC.