What is it? = an interrogative What's up? = slang, a form of greeting of non-specific meeting. It can be understood, vaguely, as "Hello." or "How or you?" or it can be understood to be an insult, such as a vulgur expression meaning "Piss off!" or "Get Lost!" .

When you ask "What is it?", you are asking someone to identify what something is. Is it a book? Is it a chair? Is it a necklace? If someone says something like "I feel.... well..." where they haven't finished their sentence, you can also ask "What is it? What is it that you are feeling? Is it happiness? Fear? Sadness?" "What's up?" means "How are you?" in slang.