"etmek" is normally used as a helper verb. Most of the time when you use it, it will be used with noun to form a phrasal verb of sorts. This noun can be dropped if it can be understood from context.
"yapmak" has more of the verbal sense of the action of doing/making something.
However, sometimes you just have to memorize which phrases use which verb. It is similar for people learning the difference between "to do" and "to make" in English. :)
'Ne yapıyorsun?' means 'What are you doing?' literally. 'Ne iş yapıyorsun?' would be more like a casual way of asking 'What do you do for a living?/What is your job?'. But maybe a more preferable way of asking for one's job would be 'Ne/Hangi işle meşgulsün?' or 'Mesleğin ne(dir)?'.