CARBOXYL METHYLATION OF RAB3D IS DEVELOPMENTALLY-REGULATED IN THE RATPANCREAS - CORRELATION WITH EXOCRINE FUNCTION

Several GTPases of the rab family, including rab3A, are methylesterifi ed on their carboxy terminal prenylcysteine residue. The significance of this reversible posttranslational modification for the function of rab proteins is unknown, although it has been postulated that carboxyl methylation facilitates the membrane association of prenylated protei ns through a hydrophobic mechanism. We here demonstrate, that pancreat ic rab3D undergoes developmentally regulated carboxyl methylation conc urrently with the maturation of the regulated secretory apparatus in p ancreatic acinar cells: in fetal glands, which are refractive to hormo ne stimulation, the majority of the rab3D protein was methylated, wher eas in neonatal and adult glands, which are secretory competent, only 50 % was methylated. The methylated form of rab3D was also predominant in a transplantable acinar cell tumor which displays impaired secreto ry responsiveness and morphological characteristics reminiscent of the fetal pancreas. In addition, treat ment of AR42J pancreatic acinar tu mor cells with dexamethasone to induce a regulated secretory pathway, led to a significant increase in the size of the unmethylated pool of a rab3-like protein. Strikingly, membrane preparations from adult panc reata and parotid glands contained both methylated and unmethylated fo rms of rab3D indiscriminately. These results suggest that the acquisit ion of stimulus-secretion coupling by the exocrine pancreas correlates with the methylation state of rab3D, and that carboxyl methylation pl ays no significant role in enhancing the membrane association or deter mining the subcellular distribution of rab3D.