Synthesis involves various biosynthetic pathways, and happens in specific time and place. Signal molecules may be released from the cell and sometimes they are not released at all, such as cellular localization signals and DNA damage signals. Such intracellular signaling networks work within the cell. Signal molecules that can be released through various ways like membrane-diffusion, exocytosis or cell damage. In some cases the signal molecules remain attached with cell-surface, a mode that helps in juxtacrine signaling (discussed below). Sometimes signal molecules require activation, such as through proteolytic cleavage or covalent modifications.