Cell adhesion regulates gene expression at translational checkpoints in human myeloid leukocytes

Engagement of adhesion molecules on monocytes and other myeloid leukocytes, which are effector cells of the innate immune system, not only tethers the leukocytes in place but also transmits outside-in signals that induce func tional changes and alter gene expression. We found that a subset of mRNAs t hat are induced or amplified by adhesion of human monocytes to P-selectin v ia its surface ligand, P-selectin glycoprotein 1, have characteristics that suggest specialized translational control. One of these codes for urokinas e plasminogen activator receptor (UPAR), a critical surface protease recept or and regulator of cell adhesion and migration. Although UPAR transcripts are induced by adhesion, rapid synthesis of the protein uses constitutive m RNA without a requirement for new transcription and is regulated by mammali an target of rapamycin, demonstrating new biologic roles for the signal-dep endent translation pathway controlled by this intracellular kinase. The syn thesis of UPAR in monocytic cells is also regulated by eukaryotic translati on initiation factor 4E, a second key translational checkpoint, and phospho rylation of eukaryotic translation initiation factor 4E is induced by adhes ion of monocytes to P-selectin. Translationally controlled display of UPAR by monocytes confers recognition of the matrix protein, vitronectin. Adhesi on-dependent signaling from the plasma membrane to translational checkpoint s represents a previously unrecognized mechanism for regulating surface phe notype that may be particularly important for myeloid leukocytes and other cells that are specialized for rapid inflammatory and vascular responses.